research opportunities 2015-2016 · together with dr. john pinto i am interested in the metabolism...

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RESEARCH OPPORTUNITIES

2015-2016

Table of Contents

Department of Biochemistry and Molecular Biology . ....... 2

Department of Cell Biology and Anatomy .......................... 6

Research Departments ......................................................... 13

Emergency Medicine ...................................................... 13

General Medicine ............................................................ 14

Nephrology ....................................................................... 14

Obstetrics and Gynecology ............................................ 15

Opthalmology .................................................................. 15

Orthopedic Surgery ........................................................ 16

Pathology.......................................................................... 16

Pediatrics.......................................................................... 18

Department of Microbiology and Immunology ................ 20

Department of Pathology..................................................... 27

Department of Pharmacology ............................................. 30

Index of Investigators .......................................................... 36

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Research OpportunitiesAcademic Year 2015-2016

BIOCHEMISTRY AND MOLECULAR BIOLOGY

Faculty Member: Arthur J.L. Cooper, PhD Laboratory Location: A03

Ongoing Research:

Transglutaminases (TGs) are involved in covalently cross linking proteins through a glutamine to lysine

bridge. I am interested in the mechanisms whereby TGs may contribute to neurodegenerative diseases.

Enzymes of the mercapturate pathway are normally involved in detoxification. Potentailly toxic

endogenous or exogenous (e.g. certain drugs) are converted to the coresponding N-acetyl cysteine

conjugate (mercapturate) and excreted in the bile or urine. However, on occassion, certain PLP enzymes

may act with the mercapturate pathway to toxify certain electrophiles. I am interested in how this

combination may contribute to mitochondrial damage with aging and adverse reactions to certain drugs

and xenobiotics.

Together with Dr. John Pinto I am interested in the metabolism of selenium-containing amino acids and

how these may contribute to chemoprevention (i.e. resistance to cancer).

Faculty Member: Marietta Lee, PhD Laboratory Location: BSB-120

Ongoing Research: Our studies represent a continuation of our long-term goals of understanding the enzymology and

functions of DNA polymerase δ (δ).

The main themes of our ongoing research are:

the characterization and identification of the subunits of human pol δ and its accessory proteins, with

the goal of understanding the functional architecture of the mammalian replication complex

the investigation of the molecular linkages between regulatory systems that control cellular DNA

replication and pol δ. These studies build on previous and current ongoing work in our laboratory

during which time we have developed the tools and necessary expertise.

There are three topics that represent almost unexplored areas of investigation that a student might work

on for a rotation. These are:

the role of S-phase cyclin/cdks in the regulation of pol δ

the phosphorylation of pol δ in relation to DNA damage checkpoint controls

the role of protein phosphatases in the regulation of pol δ.

These three aims are linked by our preliminary data which identify key signaling systems that are likely

to be involved in the cellular control of pol δ by phosphorylation/dephosphorylation mechanisms. The

attempt is now timely with the characterization of the basic pol δ subunit structure, and by the

development of the systems and tools needed to accomplish the study.

Faculty Member: Susan C. Olson, Ph.D. Laboratory Location: BSB-116A

Ongoing Research: The vascular endothelium plays a critical role in regulation of pulmonary vascular tone, growth and remodeling through the release of vasoactive mediators such as angiotensin II (Ang II) and nitric oxide (NO). We have shown that Ang II stimulates pulmonary artery endothelial cells (PAECs) to produce NO, a potent vasodilator. Data obtained thus far suggests that Ang II stimulates Src tyrosine kinase via a

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pertussis toxin-sensitive G protein-linked type 2 receptor (AT2), which, in turn, activates the MAPK pathway resulting in increased nitric oxide synthase (NOS) protein expression. Furthermore, signaling via the type 1 receptor (AT1) negatively regulates NO production. The long-term goals are to determine, at the biochemical and cellular level, the mechanisms by which both the AT1 and AT2 receptors regulate NO production and to investigate a physiological role for these receptors in regulating pulmonary vascular tone. First, we propose to identify the signaling pathway that links the AT2 receptor to Src activation, and to determine the mechanism by which Src activates MAPK will be investigated. The components of the AT1 receptor-linked pathway that inhibits eNOS expression will be investigated. And finally, the physiological role of these Ang II receptors in regulating vascular tone in intact pulmonary arteries and in established animal models of hypertension (hypoxia- and monocrotaline-induced) will be investigated. The components of the AT1 and AT2 receptor–linked pathways will be identified by treating PAECs with pharmacological inhibitors, small interfering RNAs and antisense oligonucleotides, and inhibitory peptides/proteins. The mechanism of Ang II-activation of these signaling components will be investigated by isolation of subcellular fractions using differential centrifugation; immunofluorescent confocal microscopy; GST-fusion pull-down assays; and co-immunoprecipitation. Endothelial dysfunction is a common and early indicator of future cardiovascular diseases, and may be associated with the pathological of diseases such pulmonary hypertension, diabetes, and atherosclerosis. Thus, these studies would be expected to identify new targets for the therapeutic intervention in a number of cardiovascular diseases that involve endothelial dysfunction.

Faculty Member: John Thomas Pinto, Ph.D. Laboratory Location: BSB-A03

Ongoing Research: Dr. Pinto’s research focuses on mechanisms by which diet-derived factors prevent primary and secondary

prostate cancer development. In particular, human prostate cancer cells are used to study epigenetic

pathways influenced by specific phytonutrients. Organosulfur and organoselenium compounds are

investigated that regulate cell growth and metabolism by modifying signal transduction pathways through

sulfhydryl-disulfide interactions and that inhibit histone deacetylation. Inhibitors of histone deacetylases

are highly sought after compounds to control diseases where inappropriate gene activation is a causal

feature, namely in cancer prevention and control.

Current chemopreventive studies on diet-derived organoselenium amino acids have focused on the

incorporation of selenium into antioxidative selenoproteins such as glutathione peroxidases and

thioredoxin reductases. Other biochemical mechanisms that contribute to their chemoprotective effects

involve cell specific transformations catalyzed by β- or γ-lyases resulting in generation of methylselenol.

Studies suggest that the chemopreventive activity of methylselenol resides in its ability to modulate thiol

moieties on redox-responsive signal proteins thereby maintaining a non-proliferative intracellular

environment. Our current studies have identified a more direct influence of dietary organoselenium amino

acids on the genetic and epigenetic mechanisms that impact cancer development. In particular, we show

that seleno keto acid metabolites of methylselenocysteine (MSC) and selenomethionine (SM) are potent

histone deacetylase (HDAC) inhibitors. Human glutamine transaminase K specifically catalyzes

transamination of MSC to form methylselenopyruvate (MSP) and human glutamine transaminase L

catalyzes transamination of SM to form keto-γ-methylselenobutyrate (KMSB). Both keto acids are potent

inhibitors of HDAC 1, 2, 3 and 8 activity in a dose-dependent manner. Thus, MSP and KMSB are

potential direct-acting metabolites of dietary selenium that lead to de-repression of silenced tumor

suppressor proteins and/or responses to signal factors. These studies provide novel paradigms by which

naturally-occurring organoselenium compounds may function in disease prevention and control.

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Faculty Member: Esther L. Sabban, PhD Laboratory Location: BSB-137

Ongoing Research: The molecular basis of the neurochemical responses to stress. We are examining transcriptional

mechanisms of changes in gene expression in the various neuronal locations in the brain and periphery involved in synthesizing catecholamine neurotransmitters.

What are the differences between responses to acute and repeated exposure to stress?

Our work indicates that consecutive switches in transcription factors, depending on the duration or

repetition of the stress stimuli, may underlie the mechanisms whereby acute beneficial adaptive responses

to stress are converted into prolonged physiologically damaging responses. We are examining the

induction and/or phosphorylation of several transcription factor pathways, which are shown to regulate

catecholamine biosynthesis, following different duration of stress. We are expanding the analysis by

microarray techniques.

How do the various catecholaminergic locations respond differently to stress?

What are the transcriptional mechanisms involved? We have shown important differences in the

responses of tyrosine hydroxylase in adrenal medulla, sympathetic ganglia and locus coeruleus of the

brain. One aspect of our work is testing the hypothesis that ACTH (adrenocorticotropic hormone) plays a

crucial, perhaps direct, role in the regulation of the sympathetic nervous system, especially during stress.

If proven correct, this would be a novel role for ACTH.

What are the mechanisms responsible for the large variation in susceptibility to stress?

Novel heterotypic stressor in animals adapted to one type of stress – We are examining the mechanisms

by which prolonged exposure to one type of stress, such as cold stress, leads to an exaggerated response

when animals are subsequently to a different or heterotypic stress. How are the stress responses in

catecholaminergic cells modulated by estrogen and by prior exposure to nicotine (smoking)?

Study the molecular mechanisms, using cell culture and in vivo techniques, of regulation of gene

expression for enzymes involved in catecholamine biosynthesis [dopamine beta-hydroxylase (DBH),

tyrosine hydroxylase(TH) and GTP cyclohydrolase I (GTPCH, the rate limiting enzyme biosynthesis of

tetrahydrobiopterin, the cofactor for TH, as well as tryptophan hydroxylase, phenylalanine hydroxylase

and NO synthase)]. Specifically effects of:

Estrogens: Investigate mechanism by which estrogen alters gene expression of enzymes involved in

catecholamine biosynthesis. Determine the differential responses to different estrogen receptor

subtypes (ERα and ERβ). Characterization of the gene promoter motifs responsive to estrogen or

selective estrogen agonists. Study the interaction between estrogens and the cAMP/calcium

mediated regulation of these genes.

Nicotine: Our laboratory has carried out many studies indicating that with nicotine treatment, the

prolonged release of intracellular stores of calcium, from IP3 and/or ryanodine sensitive stores,

and the activation alpha 7 nicotine receptor subtypes are involved in regulation of TH gene

expression. Experiments are directed to determining the signaling pathways triggered in cell

culture by exposure to nicotine or specific nicotine receptor agonists leading to regulation of

transcription of the TH gene. We are testing the involvement of both transcription factors CREB

and ATF-2 and the signaling pathways leading to their phosphorylation and activation, and using

siRNA knockdown components of this pathway.

Study how several of the transcription pathways activated by stress, particularly those involving CREB,

Egr1 and AP1 transcription factors regulate TH and DBH and the interactions among them.

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Faculty Member: Joseph M. Wu, PhD Laboratory Location: BSB-133, 102

Ongoing Research: Studies of quinone reductase 2 (QR2) as a novel target of chemoprevention and cardioprotection by resveratrol -- We have been studying resveratrol as a preventive agent for prostate cancer and other chronic diseases. Previous studies from this laboratory first demonstrated bioactivity of resveratrol against hormone-dependent and hormone-refractory prostate cancer (CaP) cells. This form of malignancy is a significant public health problem responsible for >30,000 deaths in American men each year. Early stage androgen-dependent (AD) CaP responds to and benefits from surgery and androgen-ablation therapies. Inevitably, the cancer recurs, accompanied by emergence of the hormone refractory state (HRPC, also known as androgen-independent prostate cancer, AI), which is usually fatal. Because the transition from AD-to-AI has a long latency, treatments by which this incubation period can be further extended could result in chronic instead of fatal CaP. Our studies on resveratrol raise the possibility that it is a viable chemopreventive option against CaP.

The mechanism of chemoprevention and cardioprotection by resveratrol remains largely unknown.

Analysis of its chemical structure suggests that resveratrol can bind to target proteins (RTPs) in a cell-

type and dose dependent manner. Multiple cellular responses - from enzyme activity/function changes, to

signaling modulation, to regulation of gene expression - may follow in sequence. Binding studies

performed several years ago in this laboratory using labeled resveratrol supported this idea and pointed to

the existence of resveratrol target proteins. We have tested this idea by chemical coupling of resveratrol to

epoxy-activated agarose beads to generate an affinity matrix that selectively retain RTPs. One such RTP

has been cloned and identified as quinone reductase 2 (QR2). We have developed QR2 knockdown and

over-expressed QR2 cell lines to learn more about the role of QR2 in chemoprevention of CaP and in

cardioprotection. In addition, we have initiated studied to learn more about the nature and identity of QR2

interacting proteins.

Faculty Member: Zhongtao Zhang, PhD Laboratory Location: BSB-107

Ongoing Research:

Neurological Disorders related to Aging, such as Parkinson's disease, are the main focus of my

laboratory. We have proposed a new paradigm for neurodegeneration and we are integrating many

proteins into the new theory, including Parkin, DJ-1, Pink1, LRRK2, Synuclein, UCHL1 and a number of

other proteins involved in the chemical detoxication process, such as QR2, NNMT, QR1 and ABAD. We

take multiple approaches in our research, including structure determination by x-ray crystallography;

functional studies with RNAi, and enzymatic characterization.

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CELL BIOLOGY AND ANATOMY

Faculty Member: Praveen Ballabh, MD Laboratory Location: BSB-205

Ongoing Research: The germinal matrix, located in the thalamostriate groove beneath the forebrain ependyma, is a richly vascularized collection of neural precursor cells, which persists until late gestation. Germinal matrix hemorrhage is a major complication of prematurity that predisposes premature infants to mental retardation, cerebral palsy and hydrocephalus. Our lab is focused to determine the pathogenesis of germinal matrix hemorrhage and to use a mechanism-based strategy to prevent germinal matrix hemorrhage. Since germinal matrix hemorrhage is not a completely preventable disorder, we are also working on neuroprotection in a rabbit model of germinal matrix hemorrhage.

Recently we have shown that vascular endothelial growth factor (VEGF), angiopoietin-2 and endothelial

proliferation are consistently higher in the germinal matrix than the white matter and cortical mantle in

human fetuses, premature infants and premature rabbit pups, and that prenatal celecoxib (COX2 inhibitor)

or ZD6474 (VEGFR2 inhibitor) suppresses the incidence of germinal matrix hemorrhage in premature

rabbit pups. We are now ascertaining the optimal dosing regimen of prenatal COX-2 and VEGF-receptor

(VEGFR2) inhibitors that is safe and efficacious in preventing germinal matrix hemorrhage in premature

newborns. In addition, we are evaluating mechanism(s) of regulation of VEGF and angiopoietin-2 in the

germinal matrix relative to other brain regions and the molecular links by which COX-2 and VEGF

inhibition is attended by a reduction in germinal matrix hemorrhage-intraventricular hemorrhage. Taken

together, our lab is working on prevention of germinal matrix hemorrhage and post-hemorrhagic

complication in premature infants.

Faculty Member: Joseph D. Etlinger, PhD Laboratory Location: BSB-237

Ongoing Research: The proteasome is a large multicatalytic proteolytic complex involved in diverse processes including the cell cycle, gene expression, inflammation, antigen processing and cell growth. We are studying regulatory proteins that associate with proteasomes and how modification of these components may influence protein turnover and other metabolic function in muscle as well as erythroid cells. We are also examining the ability of various diverse physiological and pathological factors including adrenergic agonists and radiation to modulate nerve and muscle growth and degeneration. The studies utilize animal and tissue culture models of muscle atrophy, muscular dystrophy and spinal cord injury.

Faculty Member: Victor A. Fried, PhD Laboratory Location: BSB-236

Ongoing Research: My lab is interested in posttranslational regulation and cellular states as defined quantitatively and qualitatively by the proteome. We are pursuing these problems using multidisciplinary approaches of protein biochemistry, immunochemistry and genetics. Three current projects are:

Studying the regulation of ubiquitination by specific isopeptidases.

Ubiquitination plays a central role in regulating protein degradation, multiprotein assembly, and

intracellular trafficking and the selective removal of ubiquitin by specific isopeptidases is essential to

these events. Accumulation of ubiquitin conjugates is characteristic of many diseases and we hypothesis

that this is due to a defect in the deconjugation pathways. Using specific ubiquitin conjugates as

substrates, we have discovered a new class of these isopeptidases and are characterizing their molecular

properties and regulation.

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Defining the proteome of a simple organism.

We hypothesis that the state of an organism and the mechanisms that regulate transitions in cellular states

can be determined from its proteome. We are defining the proteome of the bacterium, Borrelia

burgdorferi, as a test of this hypothesis. This organism, the causative agent of Lyme disease, has a small

genome and the gene products can be identified using 2D gel analysis and MS techniques. We have

determined that many of the proteins are extensively posttranslationally modified and that these

modifications appear correlated with the pathogenicity of this microbe. We are identifying the types of

modifications, the systems responsible for these modifications, and how these pathways are regulated.

Posttranslational modifications in glaucoma.

Previous studies have determined that many individuals with glaucoma develop a defect in the activity of

the enzyme, 3alpha-hydroxysteroid dehydrogenase. These individuals appear to have the same amount of

the enzyme and do not have a change in the coding sequence compared to individuals that do not have

glaucoma. We have discovered that the immunological properties of this enzyme are altered in glaucoma

and hypothesis that this is due to posttranslational modifications that may contribute directly to the

disease. We are identifying the nature of this posttranslational modification and the pathways that

regulate it. Such knowledge could lead to an early diagnostic and the discovery of novel therapeutic

targets.

Faculty Member: Frances Hannan, PhD Laboratory Location: BSB-204

Ongoing Research: My lab is interested in the molecular mechanisms underlying complex processes such as learning & memory and auditory function. We utilize molecular biology, genetics, and imaging to study nervous system function in the fruit fly Drosophila melanogaster.

The main focus of the lab is a Drosophila model for Neurofibromatosis Type I (NFI). This common

human genetic disorder causes disfiguring skin tumors and learning disabilities, and increased risk of

malignant tumors. We have expressed the human NF1 protein in Nf1-/- mutant flies to determine the

domains of NF1 that control Ras versus cAMP signalling pathways. We assay olfactory learning and

memory in adult flies and larvae using electric shock paired with odors. We also assay spatial learning in

flies using a “flight simulator” to train flies to respond to visual cues paired with laser punishment. We

are screening for drugs that rescue learning defects in Nf1-/- mutant flies and larvae. In addition we

perform microarray analysis and real-time PCR of gene expression profiles in Nf1-/- mutants. We are also

looking for learning defects in flies expressing mutant human Huntingtin proteins, to model cognitive

deficits of Huntington’s Disease and provide a system to screen for drugs and genetic modifiers. We have

also been looking at the effects of traumatic brain injury on survival and behavior of flies, and assessing

the protective effect of drugs affecting the polyol pathway.

We study hearing in Drosophila using an electrophysiological assay to detect a flies response to the

Drosophila courtship song. We have observed hearing defects in flies with mutations in genes that are

related to several human/mouse hereditary hearing loss genes including NF2, ESPN, TMHS and DIAPH.

We are using RNAi to specifically knockout these genes in the flies' auditory organ. We also use 2-

photon fluorescence imaging to identify structural defects in these flies, since these proteins affect actin

polymerization and microtubule stability. In addition we perform real time in vivo imaging of the

auditory organ to observe Ca2+ transients and movement of GFP labeled proteins. Finally, we are

adapting the flight simulator apparatus to look for balance defects in flies with hearing defects that are

identified in our screen.

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Faculty Member: Jian Kang, MD, PhD Laboratory Location: BSB-220

Ongoing Research: Research in my lab mainly focus on three aims:

Interplay between glial cells and neurons Kainate receptor-mediated modulation of GABAergic synapses

activity-dependent potentiation of intrinsic neuronal excitability.

For the first aim, we are investigating roles of astrocytic glutamate release in epileptic seizures,

mechanism underlying glutamate-stimulated astrocytic glutamate release, and roles of astrocytic

glutamate release in synaptic plasticity. For the second aim, we are studying kainate receptor-mediated

potentiation and depression of GABAergic synapses, activity-dependent modulation of GABAergic

synaptic transmission, astrocytic glutamate release-induced KA receptor-mediated modulation of

GABAergic synapses. In the last aim, we are working on activity-dependent modulation of Na channel

kinetics and induction pathways. Techniques we are using in our work include dual patch-clamp

techniques in synaptically connected cell pairs in hippocampal slices, two-photon laser scanning

microscopy in slices to detect Ca and other dye fluorescence in cells and vacuoles/vesicles, electronic

microscopy (EM) to detect ultrastructure of vacuoles/vesicles in astrocytes, immunoassay of glutamate-

stimulated astrocytic vacuoles.

Faculty Member: Ken Lerea, Ph.D. Laboratory Location: BSB-227A

Ongoing Research: Glyprotein IIb-IIIa (GPIIb-IIIa) is a multifunctional receptor/integrin whose structural state determines whether blood platelets attach to exposed subendothelial matrices, form stable aggregates, or briefly roll and return to the blood flow. Phosphorylation of beta3 on threonine- residues 753 (thr753) and 751 (thr751) may regulate its functions; however, it has not been established how this phosphorylation is linked to beta3 activity. We are conducting studies to understand the temporal relationship of threonyl phosphorylation of this subunit to the aggregatory function of GPIIb-IIIa. Using phoshpho-specific antibodies that were generated in the lab, we show that phosphorylation of thr753 is transient reflecting the activities of three protein seryl/threonyl phosphatases; PP1, PP2A, and PP2B. In contrast, stable phosphorylation of thr751 occurs, but only under conditions when calpains (cellular calcium-activated proteases) become actived. The phosphorylation of this site correlates with the shedding of procoagulant microparticles. We are currently studying the relationship between threonyl phosphorylation of the integrin and microparticle formation. In addition, we are addressing whether signal transduction pathways are intact in microparticles; allowing to assess whether circulating forms of "mini-platelets" are potential targets for anti-thrombotic agents.

Faculty Member: Stuart A. Newman, Ph.D. Laboratory Location: BSB-244

Ongoing Research: Mechanisms of skeletal pattern formation in the vertebrate limb.

We are testing a model for development of the vertebrate skeleton involving the interplay of morphogens

such as TGF-betas and FGFs, various FGF receptors, and extracellular matrix proteins such as

fibronectin. The experimental system is the chicken embryo and studies are conducted on embryonic

limb cells in culture and on the intact developing limb in ovo.

Mathematical and computational modeling of this developmental patterning process is ongoing, in

collaboration with several groups at other institutions. This aspect of the project plays an important role

in the design of our experiments and there will be some (limited) opportunity for rotation students to

become involved with it.

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Neodifferentiation of brown adipocytes.

Mammals produce two kinds of fat cells: white fat, characteristic of the adult body, stores energy- rich

lipids for metabolic and biosynthetic use; brown fat, more prevalent at fetal and newborn stages, is used

to generate body heat by virtue of assembly of an uncoupling protein (UCP) of oxidative phosphorylation

in the brown adipocyte mitochondria. We have found that birds lack UCP1 but contain all other essential

components of the brown adipocyte differentiation pathway. We are exploring the developmental and

evolutionary consequences of this discovery.

Faculty Member: Pravin B. Sehgal, MD, PhD Laboratory Location: BSB-201

Ongoing Research: Membrane-associated trafficking of STAT3 STAT-family transcription factors are classically viewed as transducing cytokine- and growth factor-

activated signals from the plasma membrane to the cell nucleus for the purpose of activating transcription.

We report live-cell imaging studies of fluorescently-labeled STAT3 expressed in Hep3B hepatocytes

which reveal interleukin-6 (IL-6)-activated targeting of STAT3 and PY-STAT3 to relatively long-lived

sequestering endosomes in the cytoplasm. This targeting was rapid but transient, required

phosphorylation and integrity of Tyr-705 in STAT3 and was blocked by nocodazole, geldanamycin and

indirubin E804 and by overexpression of wild-type caveolin-1. Strikingly, overexpression of the

dominant-negative (DN) mutant K44A of the GTPase dynamin II led to marked constitutive

accumulation of STAT3 in the endocytic compartment with depletion of the STAT3 nuclear pool. Subsets

of the native and K44A- generated STAT3- and PY-STAT3 sequestering endosomes colocalized with

MyD88, an adapter protein which integrates pathways of Toll-like receptor (TLR) and interleukin-1 (IL-

1) transcriptional signaling and for stabilization of mRNAs. These data provide direct evidence for the

cytokine-induced “signal transduction” by STAT3 from the plasma membrane to a cytoplasmic

membrane destination for yet to be elucidated function(s) in the cytoplasm including prolongation of

signaling and/or cross-talk.

Pulmonary arterial hypertension: a disease of tethers, SNAREs and SNAPs?

Discussions of the initiation of pulmonary arterial hypertension (PAH) in man and in experimental

models have centered around intimal and medial proliferation in medium-sized pulmonary arteries. The

histologic events are thought to include disordered proliferation of enlarged, vacuolated endothelial cells

and neo-muscularization of the affected blood vessels and vascular pruning. The discovery of the

association of familial and sporadic PAH with mutations in BMPR2 has generated intense interest in

cytokine receptor trafficking and function in the endothelial cell and how this might be disrupted to yield

an enlarged proliferative cell phenotype. Nevertheless, considerations of the subcellular machinery of

membrane trafficking in the endothelial cell and consequences of the disruption of this outward and

inward membrane trafficking are largely absent from discussions of the pathobiology of PAH. Long-

standing electron microscopy data in the PAH field evidencing marked disruptions of intracellular

membrane trafficking in human and experimental PAH, the discovery of a role of the membrane-

trafficking regulator Nef in simian HIV-induced PAH in macaques and in HIV-induced PAH in man, the

disruption of the function of Golgi tethers, SNAREs, SNAPs and N-ethylmaleimide sensitive factor

(NSF) by monocrotaline and hypoxia (the Golgi blockade hypothesis), and the trapping of PAH-

associated human BMPR2 mutants in the Golgi compel us to consider the implications of disrupted

intracellular membrane trafficking in the pathobiology of this disease. Recent studies from this lab

indicate a pathogenetic role of the disruption of intracellular trafficking of vasorelevant proteins and cell-

surface receptors in the development of this disease. We highlight the molecular regulation of vesicular

trafficking by membrane tethers, SNAREs and SNAPs and to suggest how their dysfunction, directly

and/or indirectly, might contribute to development of PAH in experimental models and in man, including

that due to mutations in BMPR2.

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Faculty Member: Sansar Sharma, Ph.D. Laboratory Location: BSB-249

Ongoing Research: My laboratory is interested in the mechanism of retinal-ganglion cell death with experimentally induced

glaucoma. We are specifically interested in the cell-signaling cascade that leads to the regulation of

apoptosis during glaucoma. In addition we are interested in the changes occurring in brain connectivity

patterns during the development of glaucoma. A variety of sophisticated techniques including molecular

biological and biochemical, electrophysiological and behavioral protocols are currently in use.

Faculty Member: Alan D. Springer, Ph.D. Laboratory Location: BSB-231

Ongoing Research: Virtual engineering simulations of the mechanisms underlying retinal and foveal development; causes of retinal detachments in premature infants; causes of strabismus.

Faculty Member: Patric K. Stanton, Ph.D. Laboratory Location: BSB-217

Ongoing Research: My lab is interested in the cellular mechanisms of synaptic plasticity that underlie learning and memory,

and how these mechanisms contribute to neuropathologies such as epilepsy and stroke- induced delayed

neuronal death. For 16 years, we have been engaged in work across the range of neuronal plasticity,

including: 1) properties of long-term activity-dependent potentiation (LTP) and depression (LTD) of

synaptic strength; 2) links between LTD and cascades underlying LTP; changes in synaptic function

associated with the development of epileptic seizures; and 4) cellular mechanisms that both trigger and

prevent ischemia-induced delayed neuronal death. We were the first to show that induction of mammalian

LTP requires cyclic AMP and new protein synthesis, and to demonstrate a novel form of LTD evoked

when presynaptic inputs are active while postsynaptic neurons are hyperpolarized. This led to our

describing a NO-mediated cyclic

GMP-dependent biochemical cascade that is part of bi-directional cyclic nucleotide regulation of synaptic

strength, discovering chemical methods of inducing this and other forms of LTD, and direct two-photon

fluorescence imaging of presynaptic transmitter release to demonstrate that this form of LTD persistently

modulates release from the rapidly-recycling pool of transmitter vesicles. We employ extracellular and

whole-cell patch clamp recordings, two-photon excitation and confocal fluorescence imaging in both

acute and organotypic cultures of in vitro slices from hippocampus and neocortex. As a more

physiologically intact network of synaptically connected neurons and glia, brain slices are ideal for the

study of cellular and synaptic properties of neural systems.

Faculty Member: Libor Velisek, MD, PhD Laboratory Location: BSB-A20/A04

Ongoing Research: We focused our research on investigation of the animal model of infantile spasms, a devastating epilepsy syndrome of childhood associated with cognitive decline. Our animal model includes prenatal elevation of corticosteroids and postnatal trigger of spasms using N-methyl-D-aspartic acid. By combination of these two factors in rats, we were able to human replicate infantile spasms semiologically, in EEG traits, and also in their response to therapy using adrenocorticotropin (ACTH), corticosteroids, or vigabatrin. Currently we are dissecting molecular and synaptic mechanisms involved in the increased susceptibility of the model to spasms and also mechanisms of efficacy of ACTH against the spasms. Our results indicate that hypothalamic system including arcuate and paraventricular nuclei is impaired after prenatal corticosteroid boost and various changes in the expression of hypothalamic peptides (such as CRF) and

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their receptors (such as melanocortin 4 - MC4) develop. Results of testing of additional drugs acting on upregulated MC4 receptors suggest that that novel treatments of infantile spasms may include specific agonists of MC3/MC4 receptor isoforms.

In collaboration with Columbia University, we explore synaptic and molecular mechanisms associated

with a mouse model of Idiopathic Generalized Epilepsy (IGE; and Juvenile Myoclonic Epilepsy in

particular). Dr. Greenberg (Columbia) found that IGE in humans is associated with BRD2 gene. Using a

vector trap, the Brd2 deficient (heterozygous) mouse was created. This model replicates well human IGE

in the phenotype (increased susceptibility to provoked seizures as well as development of spontaneous

seizures and sex specificity) and also indicates that down regulation of inhibitory transmitter GABA

along the basal ganglia pathway may be one of the culprits of increased seizure susceptibility in Brd2

heterozygote mice and likely in humans.

Methods used in the lab include in vitro electrophysiology (extracellular and pathc clamp), western blot

and autoradiography, histology, immunohistochemistry, intracranial drug administration, long-term

video/EEG monitoring, behavioral testing (learning, memory, anxiety, motor behaviors), and gene-chip

profiling.

Faculty Member: Jana Veliskova, MD, PhD Laboratory Location: BSB-A21/A04

Ongoing Research:

Dr. Jana Veliskova is investigating mechanisms by which sex hormones influence neuronal excitability

during physiological conditions such as synaptic plasticity and during pathological processes including

seizures and seizure-induced damage. About 40% of women with epilepsy have catamenial type of

epilepsy, a condition during which seizures tend to cluster in relevance to menstrual cycle. Although it

has been believed for decades that estrogens induce excitatory actions in the CNS, recent studies

including our data show that estrogens act not only as an excitatory but also as an inhibitory agent.

Further we found that loss of estradiol enhances propensity to seizure-induced hippocampal damage,

which can be prevented by replacement with estradiol within physiological levels. The seizure-

modulating and neuroprotective effects seem to be associated with estradiol-induced filtering of

frequency-dependent activity of the gatekeeping

dentate granule cells.

We also found that the estradiol-dependent frequency-specific activity filtering plays an important role in

the expression of long-term synaptic plasticity in the hippocampal dentate gyrus. Thus, estradiol has

frequency-specific effects on LTP and produces metaplastic effects, which involve interactions between

metabotropic glutamate receptors and NR2B subunit-containing NMDA receptors. These findings are

important for mechanistic understanding of estradiol- induced neuroprotective effects and development of new treatment strategies to prevent cognitive decline in menopausal women.

Techniques used in the laboratory to study estradiol effects include (but not limited to): different seizure

models, in vivo intracerebral drug infusions, learning and memory tests, in vivo LTP induction, in vitro

extracellular recordings, patch clamp recordings, two-photon calcium imaging and pre-synaptic

transmitter release, western blot, immunohistochemistry, staining for damaged neurons.

Faculty Member: Richard Zeman, PhD Laboratory Location: BSB-242B

Ongoing Research: An important goal of rehabilitation following spinal cord injury is to promote recovery of locomotor function. Currently, the amount of recovery of locomotor function following incomplete spinal cord injury is thought to depend, in part, on the extent of inflammation occurring in the injured spinal cord

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tissue. Because inflammation generates reactive oxygen species (ROS), which denature cellular constituents leading to cell death, oxidative processes can limit the amount of tissue spared following injury and ultimately the number of surviving functional axons capable of supporting locomotor recovery. Therefore, an approach toward enhancing recovery from spinal cord injury is to optimize the capacity of the spinal cord to oppose ROS-mediated neurodegeneration.

We determined whether the β2-agonist and anti-inflammatory agent, clenbuterol, can improve recovery

of locomotor function following spinal cord injury. A model of spinal cord injury was examined in which

four graded levels of contusion injury were produced in rats at the level of T10 with a weight-drop

device. Locomotor recovery was determined with the BBB scale, which distinguishes 22 progressive

levels of recovery. Recovery during the 6 weeks following injury was inversely related to the severity of

injury. However, clenbuterol caused substantial enhancement of recovery of locomotor function at the

two most severe levels of injury (final BBB scores 10-12 vs 2-4). In addition, the extent of recovery was

directly related to sparing of spinal cord tissue at the contusion center.

Agents, such as clenbuterol, that oppose neurodegeneration and improve recovery of locomotor function

may act by improving redox status. Consistent with reduced oxidative stress by β2 agonist treatment

following injury, prior blockade of synthesis of the antioxidant tripeptide, glutathione, with buthionine

sulfoximine completely inhibited the ability of clenbuterol to enhance locomotor recovery and spare

spinal cord tissue. Furthermore, clenbuterol caused an increase in glutathione reductase activity, an

indicator of cellular redox status, at the injury site that was also blocked by buthionine sulfoximine.

Although clenbuterol improved locomotor recovery only when administered within a therapeutic window

of several days postinjury, the accumulation of protein carbonyls in the spinal cord at 1 week postinjury, a

consequence of ongoing ROS-mediated neurodegeneration, was also decreased by clenbuterol in a

glutathione- dependent manner. Together, these results indicate that activation of β2 adrenoreceptors

during the acute phase of injury stimulates glutathione-dependent antioxidative processes, that lead to

reduced oxidative damage and greater locomotor function as the injury evolves during the subacute and

chronic phases.

To further investigate the mechanism(s) of neuroprotection in this experimental model of spinal cord

injury, glutathione-dependent, β2 agonist-induced gene expression within spinal cord tissue during the

acute and subacute phases of injury will be determined with microarray and immunocytochemical

technology.

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CLINICAL RESEARCH

Emergency Medicine:

Faculty Member: Gregory Almond, M.D., M.P.H., FACEP ~ Chairman Dept of Emergency

Medicine NYMC ~ Metropolitan Hospital Center ~ Phone: 212.423.6684

Ongoing Research:

Students may develop their own projects or join existing projects. Students considering

this program are encouraged to speak with Dr. Almond as early as possible, as potential new projects

take several months to process through the IRB.

The faculty of the Department of Emergency Medicine at Metropolitan Hospital Center are most

interested in working with medical students interested in participating in clinical research in Emergency

Medicine. Students will also be able to observe and work closely with the attending staff to develop a

better understanding of Emergency Medicine as a subspecialty.

It is expected that each student will complete the program with the skills necessary to perform literature

searches, write research protocols, collect data in a clinical setting and understand the concepts of

validity and statistical significance. Students will be required to attend weekly Emergency Medicine

Department Conferences and research team meetings as scheduled. As this is multi---site program, the

student may be required to travel between facilities for meetings and conferences.

Faculty Member: Michael Reilly, Dr.PH. ~ NYMC School of Public Health ~ Phone: 914-594-1740

~ Email: [email protected]

Ongoing Research:

The Center for Disaster Medicine is a program within the New York Medical College School of Public

Health in collaboration with multiple departments in the School of Medicine dedicated to research and

teaching in Emergency Preparedness with a focus on the Hudson Valley. Students will meet with Dr.

Reilly and his faculty and design a research project in Disaster Medicine. Students may participate in any

of the ongoing research projects or rarely a student may be able to design an individual research project.

Current areas of research include:

Pediatric Emergency Preparedness

Preparedness for Persons with Disabilities

Emergency Preparedness and Disaster Management for the Hudson Valley

Blast Injury

Analysis of Emergency Preparedness in other countries

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mailto:[email protected]


Medicine:

General Medicine:

Faculty Member: Robert Y. Lin, M.D. ~ Section Chief ~ New York Downtown Hospital, Manhattan

~ Phone: 212.423.5640

Ongoing Research:

With the improved formulations of gammaglobulin, there has been increasing use of this mediation in

non-immunodeficiency disorders. As it is an expensive medication which is sometimes in short supply, it

would be important to understand how physicians are ordering this drug in order to develop allocation

policies and utilization strategies. Objectives: To examine the incidence of gammaglobulin use New

York State. Trends and clinical associations will be characterized. Population based rates will be

determined.

Study methods: ICD9 coding for gammaglobulin administration will be used to identify hospitaladmission in NYS for the past 20 years using the SPARCS databased. Common diseases treated

with gammaglobulin will be tabulated to identify admission characteristics. The hospital charges

and lengths of stay will be examined for these admissions. Compilation of selected data will be

performed and data will be analyzed using statistical software programs (SPSS). Population

statistics will be based on census data for New York State.

Study site: New York Downtown Hospital, Manhattan

Goals: Presentation at a national allergy meeting with subsequent publication in a Medline cited

journal. Introduction to academic and clinical aspects of medical specialties involved in

rheumatology and immunology will also be incorporated into the elective/preceptorship.

Nephrology:

Faculty Member: Michael S Goligorsky, MD, PhD ~ NYMC-WAKF Renal Research Institute ~

Phone: 914.594.4730 ~ Email: [email protected]

Ongoing Research:

The major directions of the Renal Research Institute are summarized below.

The problem of Endothelial Cell Dysfunction is being addressed on several investigative levels.

1. Unbiased DNA microarray, proteomic and metabolomic screen of cells and microvessels followed

by the attempts at disclosing molecular mechanisms and metabolic pathways responsible.

2. The focus of these investigations is on stress-induced premature senescence (SIPS) of endothelial

cells and endothelial progenitor cells. The role of lysosomal dysfunction (collapse of pH gradient and

permeabilization of the lysosomal membrane) in triggering SIPS is under intense scrutiny. As a

consequence of lysosomal dysfunction, endothelial cells exhibit impairment in authophagic

processes, further exacerbating endothelial dysfunction.

3. The mechanisms of EPC incompetence in different models of chronic kidney disease.

The problem of Acute Kidney Injury is addressed in the following levels

1. Investigations into the mechanisms of Alarm Signaling by ischemic organ, activation of Tall-like

receptors and exocytosis of Weibel-Palade bodies

2. Laser Doppler flowmetry and Multiplex analysis of cytokines, chemokines and pro- and anti-

angiogenic factors.

3. Proteomic screen of patients with failing renal transplants

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Obstetrics and Gynecology:

Faculty Member: Camille A. Clare, MD, MPH, CPE, FACOG ~ Assistant Professor, New York

Medical College, Director of Resident Research, Department of Obstetrics and Gynecology ~

Metropolitan Hospital Center ~ Phone: 212-423-6796 ~ Email: [email protected]

Ongoing Research: Students may develop their own projects or join existing projects. Students considering this program are

encouraged to speak with Dr. Clare as early as possible, as potential new projects take several months to

process through the IRB. Student participation in an ongoing approved IRB research project is preferred.

One medical student per quarter in the academic year of July through June is preferred (four medical

students per year total) for a one month elective rotation cycle. There may be flexibility in the number of

students depending on the research projects ongoing.

The faculty of the Department of Obstetrics and Gynecology at Metropolitan Hospital Center are most

interested in working with medical students interested in participating in clinical research in obstetrics

and gynecology. Students will also be able to observe and work closely with the attending staff to

develop an understanding of other aspects of obstetrics and gynecology.

It is expected that each student will complete the program with the skills necessary to perform literature

searches, write research protocols, collect data in a clinical setting and understand the concepts of

validity and statistical significance. Students will be required to attend weekly Department of Obstetrics

and Gynecology Resident Report Conferences and research team meetings as scheduled. Occasionally,

students may be able to participate in Grand Rounds conferences in the Department of Obstetrics and

Gynecology at Westchester Medical Center depending on where the student lives. A research

presentation to the Department of Obstetrics and Gynecology at the end of the research elective month

will be required to complete the elective.

Ophthalmology: Research Opportunities are available in the following areas:

Retinal Diseases

Dan Hirsch-Kauffmann Jokl, M.D. ~ Associate Professor, Retinal Service ~ Westchester Medical

Center ~ Phone: 914.493.7671

Glaucoma shunts and glaucoma blood tests

Thaddeus Wandel, M.D. ~ Chief of the Glaucoma Service ~ Westchester Medical Center ~ Phone:

914.493.7671

Research Opportunities-General and Specialty Ophthalmology

Drs. Ritch, Ritterband, Gentile, Sidoti, Della Rocca, Finger, & Samson ~ New York Eye & Ear

Infirmary ~ Chair's Office: 212.979.4447

Corneal Diseases

Gerald Zaidman, M.D. ~ Professor, Chief of Cornea and External Disease Service ~ Westchester

County Medical Center ~ Phone: 914.493.1599

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Orthopedic Surgery:

Faculty Member: Paul Lucas, Ph.D. Associate Professor BSB-404 ~ Phone: 914.594.3222

Ongoing Research: Research in the laboratory is currently focused on Tissue Engineering. Tissue engineering, or

regenerative medicine, is a new discipline whose goal is the restoration of tissue identical to the original

following disease or trauma. We work with a unique adult stem cell called a multipotent adult stem cell

MASC) that is capable of differentiating into tissues from all three dermal layers. The work of the

laboratory focuses on characterization of the MASC and use of the PPASCs to regenerate tissues. We

have seen MASCs regenerate bone and cartilage in an articular cartilage defect and regenerate nerve in a

spinal cord. We are also investigating the hypothesis that cancer cells arise from MASCs (or some

similar cells) and retain the ability to differentiate into phenotypes of all the dermal layers. I realize that

the goal of medical students is to obtain experience and publications that will aid them in admission to a

good residency program. Therefore what we try to do is the preliminary work during the year so that

there are projects progressed far enough that the medical students can finish them during the summer

rotation. Any student who works on a project will be an author on a paper, though not necessarily the

first author. Experience has taught me that I can competently instruct only three medical students during

the summer.

This year, projects will include:

1. Differentiation of the MASCs to endodermal phenotypes, particularly pancreatic islet cells

2. Use of the MASCs to regenerate bone in a rat orthotopic defect model

3. Differentiation of a melanoma and breast cell tumor cell line to phenotypes of all 3 dermal

layers.

4. We may also (depending on grant funds) be testing the ability of MASCs to regenerate

intervertebral discs in a rabbit model.

Pathology:

Meena Jhanwar-Uniyal, Ph.D. ~ Department of Neurosurgery and Experimental Pathology

Ongoing Research: Research in the laboratory is currently focused on bridging g the gap between basic and clinical aspects

of the origin, progression, prognosis, prevention, and treatment of cancer. The goal of our laboratory is to

use increased insight into neural precursor cell cycle regulation to better understand the etiology of brain

tumors, and identify novel targets for new treatment modalities. The main focus has been to determine

the molecular and genetic determinants of cancer predisposition, tumor development and metastasis, the

nature of therapeutic targets and the basis for their response to therapy.

The cell of origin for gliomas has been disputed extensively. The glial characteristics of these tumors

could imply that they arise from the differentiated glia they resemble or their precursors. We established

stem cells from tumors, and characterize them, is context of their signaling pathways. Mutations found in

gliomas destabilize the differentiation status of these cells, rendering it difficult to determine which cell

type gives rise to a given tumor histology. We observe that undifferentiated, nestin (neural stem cell

marker) expressing cells are more sensitive to the oncogenic effects of certain signaling abnormalities

than are differentiated astrocytes. We observed that nestin is expressed heavily not only in tumor region

but also in peritumor areas, where pre neoplastic cells are seen. Medulloblastoma is the most common

malignant solid childhood tumor. These tumors arise from precursor cells of the developing cerebellum,

a brain region which undergoes rapid expansion after birth. Current treatments for these tumors include

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surgery, radiation, and chemotherapy, which cause lasting physical, cognitive, and psychological effects.

ntiated astrocytes to act as the cell-of-origin for gliomas.

Current emphasis is placed on following areas:

Characterization of Cancer stem cell from brain tumors

Mechanisms for organ---specific cancer metastasis.

The analysis of the cell signaling pathways triggered by BRCA1, PTEN, p53 and RAS proteins.

Understanding of promoter specific regulation of gene.

Our work is related to the activation of Ras/MAPK and Akt signaling in GBM invasion and proliferation.

It may be possible that these pathways act independently or in concert with each other. The requirement

for combined Ras/MAPK and Akt signaling indicates that these pathways may coordinately control some

keep steps that lead to tumors. We are now deciphering the signaling pathways downstream of Ras and

PTENAkt to establish what portions of these pathways lead to the oncogenic phenotype seen.

Importantly, we explore the involvement of mTOR, a downstream from Akt, as molecule of interest in

brain tumors. Using antibodies that recognize the activated form of proteins in the signaling pathways

downstream of Ras/MAPK and Akt, we have begun to trace hyperactivity of specific subsections of the

signal transduction pathways in human gliomas samples. The aim is to define the intersection of

Ras/ERK and Akt pathways.

Furthermore, we aim to decipher genetic alterations associated with initiation and development of brain

tumors. Also, our objective is to study the genetic mechanism(s) associated with cancer dissemination

metastatic tumors, exclusively to the brain.

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Pediatrics:

Pediatrics, Division of Medical Genetics and Biochemical Genetics:

David Kronn, M.D. ~ Director ~ Phone: 914.304.5313

Lawrence R. Shapiro, M.D. ~ Director Emeritus

Elizabeth Lim-Melia, M.D. ~ Assistant Director

Susanna Sorrentino, M.D.

Ongoing Research: Medical Genetics is an expanding specialty as the molecular etiology of more and more diseases is

understood. A summer fellowship will allow students to gain insights into the diagnosis, evaluation and

management of a range of patients with genetic disorders and inborn errors of metabolism. Students will

gain an understanding of the various methods used to evaluate patients, in particular current biochemical,

cytogenetic and molecular technologies. The Program is a referral site for Newborn Screening and this

forms the basis for our many research interests. Opportunities exist for participation in clinical research.

Upon completion of the summer program, students will have an enhanced understanding of the interface

of Medical Genetics with all areas of medicine.

Pediatrics, Division of Neonatology:

Edmund F. La Gamma, M.D. ~ Chief

Lance A. Parton, M.D. ~ Summer Program Coordinator

Gad Alpan, M.D. ~ Praveen Ballabh, M.D. ~ Heather Brumberg, M.D., M.P.H. ~ Joy Calo, M.D. ~

Sergio Golombek,M.D., M.P.H. ~ Semsa Gogcu, M.D. ~ Jordan Kase, M.D. ~ Necla Kirtok, M.D. ~

Prabakar Kocherlakota, M.D. ~ Yogangi Malhotra, M.D. ~ Myra Mercado, M.D. ~ Vanessa

Mercado, M.D. ~ Bistra Nankova, Ph.D. ~ Boriana Parvez, M.D. ~ Muhammed Zia, M.D.

Ongoing Research: A variety of ongoing projects involving basic science, clinical and translational research are offered,

based on the student's interest. Projects include: dietary effects on neuronal gene regulation, role of

thyroid hormone in brain development, molecular mechanisms of failure of glucose counter-regulation in

diabetes, developmental biology of neonatal brain injury and intraventricular hemorrhage, near infrared

spectroscopy and plethysmographic measurements in the extremely low birth weight infant, SNP

screening for risk of chronic lung disease, neonatal epidemiology, neonatal nutrition for the preterm

infant, neonatal infection from central line catheters, use of GCSF and IgG as supplemental therapy for

sepsis, prevention of transfusion associated acute gut injury (TRAGI), steroid receptor studies in the

premature central nervous system, developmental outcomes in extremely low birth infants, breastfeeding

of the preterm infant, music therapy and complementary modalities of treatment in the NICU, and

genetic foundations for neonatal conditions such as patent ductus arteriosus and bronchopulmonary

dysplasia. Collaborative projects that involve Neonatology with a number of other educational and

clinical programs are also available, including: Maternal-Fetal Medicine (Director Dr. Andrew Elimian),

which explore the genetic foundations for conditions such as cervical shortening and preterm delivery.

Pediatric Hematology (Director Dr. Mitchell Cairo) project on cord blood derived mesenchymal stem

cell therapy for hypoxic ischemic encephalopathy. Pediatric Pulmonology (Director Dr. Allen Dozor)

projects which explore genetic foundations in the responsiveness to beta-adrenergic medications;

Pediatric Cardiology (Dr. Rajma Matthews) project on pulmonary hypertension and, with our Basic

Science (Susan Olsen, Ph.D.) colleagues at NYMC with particular emphasis on pulmonary hypertension

in the newborn.

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Pediatrics, Division of Pediatric Cardiology:

Michael Gewitz, M.D. ~ Chief, Pediatric Cardiology, NYMC ~ Phone: 914.594.4370

Joseph Giamelli, M.D. ~ Summer Program Coordinator

Associate Cardiologists: Julian M. Stewart, M.D., Ph.D. ~ Karen Seligman, M.D. ~ Markus Erb,

M.D. ~ Bernard G. Fish, M.D. ~ Aaron Levin, M.D. ~ Rajamma Mathew,M.D. ~ Gilbert Herzberg,

M.D. ~ Henry Issenberg, M.D. ~ Deborah Friedman,M.D. ~ Irfan Warsy, M.D. ~ Supriya Jain, M.D.

~ Fredrick Bierman, M.D. ~ Christa Miliaresis, M.D.

Ongoing Research: Research opportunities are available in cardiovascular physiology and in pulmonary circulatory

physiology and pulmonary hypertension. Clinical research involvement may also be available in a variety

of areas including electrophysiology, cardiopulmonary interactions, echocardiography and exercise

physiology.

Pediatrics, Division of Pediatric Endocrinology:

Richard Noto, M.D. ~ New York Medical College ~ Phone: 914.36.-3400 x113

Ongoing Research: Ongoing clinical research projects are available in a variety of areas including growth hormone

deficiency, AIDS, insulin dependent diabetes mellitus, lead toxicity, and congenital hypothyroidism.

Also, students can be involved with ongoing basic science research projects. These research projects may

lead to publications and abstracts.

Pediatrics, Division of Pediatric Pulmonology, Allergy and Sleep Medicine:

Allen J. Dozor, M.D. ~ Professor of Pediatrics and Clinical Public Health Chief, Pediatric

Pulmonology, Allergy & Sleep Medicine ~ Phone: 914.493.7585 ~ Email: [email protected]

Associate pulmonologists: Agnes Banquet, M.D.; Jay Boyer, M.D.; Elizabeth de la Riva--Velasco,

M.D.; Suzette Gjonaj, M.D.; Y. Cathy Kim, M.D.; Sankaran Krishnan, M.D.; Priya S. Prashad,

M.D.; Subhadra Siegel, M.D.; Marilyn Scharbach, M.D.; Nadav Traeger, M.D.; John Welter, M.D.

Ongoing Research: Our division has a large research program primarily based on improved therapies for asthma and cystic

fibrosis. Students particularly enjoy joining our large faculty while they care for both inpatients at the

Maria Fareri Children's Hospital and outpatients in our faculty practice suite. Students are exposed to all

three areas within our division: pulmonology, allergy and pediatric sleep medicine.

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MICROBIOLOGY AND IMMUNOLOGY

Faculty Member: Chandra Shekhar Bakshi DVM, Ph.D. Laboratory Location: BSB-340

Ongoing Research:

As a trained bacteriologist for the past several years my research efforts have been devoted to understand

how bacterial pathogens create an environment permissive for their intracellular survival, growth and

virulence by modulating the host’s innate immune responses. My current research focuses on a bacterial

pathogen; Francisella tularensis, the causative agent of tularemia. Francisella is enlisted amongst the

deadliest agents of biological warfare and bioterrorism. The goal of my research is to understand how

antioxidant defenses of Francisella tularensis contribute to resistance to oxidative stress, virulence and

most importantly, immune-suppression. I employ genetic approaches to study the pathogenic

mechanisms of this bacterium. A better understanding of such mechanisms will lead to the identification

of defined subunit vaccine candidates for the prevention of tularemia acquired naturally or through an act

of bioterrorism.

Faculty Member: Ranjit Banerjee, Ph.D. Laboratory Location: BSB-346

Ongoing Research:

Effect of Cofactors on HIV-1 Gene Expression.

To evaluate the latency and tropism of human immunodeficiency virus (HIV-1) infection and the effect

of different cofactors, such as cytokines and mitogens which may act as cell signaling device using our

novel experimental cellular models. The effects of these agents are being evaluated on the replication and

transcription of HIV-1 regulatory regions and interaction of various genes by molecular analysis to

identify: i) the role of antiviral agents and ii) interaction of HIV-1 with other viruses.

Identification of Genes Controlling Lymphocytic Differentiation and Transformation.

The mechanism(s) involved in lymphocytic development which may influence on viral infection and also

malignant transformation. Various novel cell lines have been generated to isolate and characterize

specific genes and the involvement of transcription factors in this process. Modern techniques in

molecular cell biology of differentiation and signal transduction are being applied to evaluate the clinical

relevance of the modulation of cellular factors. Importance of CD4+ and CD8+ specific T cell factors in

HIV-1 gene regulation is being investigated.

Effect of Cofactors on the interaction HIV-1 and HBV Gene Expression.

Coinfection o Interaction of these two viruses and the influence of different signal transducing agents is

being investigated.

Faculty Member: Debra Bessen, Ph.D. Laboratory Location: BSB-315-18

Ongoing Research:

Our research is primarily focused on group A beta-hemolytic streptococci (Streptococcus pyogenes),

which are among the most prevalent of bacterial pathogens; humans are its sole biological host. A

hallmark feature of S. pyogenes is its molecular and biological diversity among strains. Although S.

pyogenes infection can produce serious illness, such as autoimmune and severe invasive disease, most

often it causes only a mild disease at superficial tissue sites - the oropharynx (strep throat) or epidermis

(impetigo). The throat and skin are the primary tissue reservoirs for S. pyogenes, whereby the organism is

most successful in reproductive growth and transmission to new hosts. Based on decades of field work, it

has become widely recognized that many strains differ in their tissue site preference, giving rise to the

concept of distinct throat and skin strains. Our long-term goals include understanding the underlying

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genetic organization of S. pyogenes, and determining the molecular basis for throat- and skin-specific

infections. Our approach integrates the disciplines of population genetics, population genomics and

molecular pathogenesis (bacterial mutant construction, transcriptome analysis, animal models).

In another major area of inquiry, we are investigating the role of group A streptococcal infections in

triggering acute episodes of common neuropsychiatric disorders in children (Tourette's syndrome and

chronic tic disorders, obsessive-compulsive disorder), via an autoimmune mechanism.

Faculty Member: Doris Bucher, Ph.D. Laboratory Location: BSB-303/305

Ongoing Research:

Current research on influenza in our laboratory focuses on vaccine development. This work is supported

by funding from the fourteen influenza manufacturers producing for the world influenza vaccine market.

Our laboratory is responsible for development of the high-yield reassortant strains for influenza vaccine

production. The influenza vaccine is comprised of three component inactivated viruses: two influenza

type A viruses (H1N1 and H3N2) and one type B influenza virus. Influenza vaccines are prepared from

virus grown in embryonated eggs. Since human isolates of influenza grow poorly in ovo, it is essential to

develop high yield reassortant viruses which grow well in eggs. The segmented nature of influenza

viruses permits ‘reassortment’ of the gene segments on mixed infection with two viruses. High yield type

A influenza reassortants are prepared by coinfecting embryonated eggs with the highly egg-adapted

A/PR/8/34 virus and the currently circulating influenza virus. The desired high yield virus contains the

genes for the surface antigens of the currently circulating virus along with genes for high yield in ovo

contributed by A/PR/8/34. The use of antibodies against A/PR/8/34 surface antigens prevents growth of

any virus containing A/PR/8/34 surface antigens and insures that only the high yield reassortant virus

(with the current surface antigens) replicates.

All type A influenza vaccines are currently prepared utilizing high-yielding reassortant influenza viruses;

similar reassortant viruses are needed for production of the type B component of influenza vaccine. We

have recently developed methodology utilizing a high yield B donor with a selection system which

generates type B influenza viruses which grow to high titer in ovo for vaccine production. Influenza

researchers have been attempting to make suitable high yield B reassortant viruses for more than 30

years. We have recently prepared the first high yield influenza B reassortants, NYMC BX-3 through BX-

19, to circulating B strains and submitted these viruses to the Centers for Disease Control for evaluation

for vaccine use. All of the B reassortant viruses met the antigenic standards for use in the vaccine; we

anticipate that our B reassortants will be used as part of the vaccine formulation in the near future.

In 2003, we produced NYMC X-147 (H3N2) containing ‘Fujian’ type surface antigens. This virus was

utilized in influenza vaccine formulations for the Southern hemisphere (2004 flu season) and in the

Northern hemisphere for the 2004-2005 flu season. In 2005, we prepared a new H3N2 reassortant to the

A/’California’ antigenic variant, NYMC X-157 which both the U.S., European and other countries have

used as the H3N2 component for the 2005-2006 flu vaccine. In 2006 we developed NYMC X-161B to

A/ Wisconsin which has been used for the 2006-2007 vaccine for the U.S. and many other countries as

well as the 2007-2008 vaccine worldwide. For two of the four recent annual flu vaccines, our laboratory

was the only laboratory (among several international labs) which was able to make the necessary high

yield reassortant viruses for the influenza vaccine.

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Faculty Member: Felipe C. Cabello, M.D. Laboratory Location: BSB-324

Ongoing Research:

We study molecular genetic techniques, molecular biology methods and animal models, the genes and

their gene products involved in the ability of B. burgdorferi to produce disease in human and animals. We

are especially interested in identifying borrelia genes and their products that are involved in the ability of

B. burgdorferi to persist in the extracellular matrix of the mammalian host and to survive host defenses

and antibiotic treatment. Identification of these genes and their functions will improve our abilities to

prevent and treat infections by B. burgdorferi in humans and in animals.

We are also studying the genetics of quinolones resistance in several marine bacteria, including the

human pathogen Vibrio parahaemolyticus. The goal of this project is to determine whether marine

bacteria, including vibrio, can transfer these quinolones resistant determinants to alternative human

pathogens, including Escherichia coli and Klebsiella pneumoniae. The goal of this project is to determine

whether there is sharing of antibiotic resistant determinants between bacteria of the marine environment

and human pathogens.

Faculty Member: Raymond Dattwyler, M.D. Laboratory Location: BSB lab CO4

Ongoing Research:

Research activities in our laboratory focus on emerging tick-borne infectious diseases, primarily Lyme

disease and human granulocytic ehrlichiosis. Lyme disease is the most common tick-borne disease in the

United States and is caused by infection with the spirochete, Borrelia burgdorferi. Projects include

genomic approaches to elucidating the mechanisms of B. burgdorferi pathogenesis, development of

molecular diagnostics for these diseases, determination of pathogen prevalence in natural tick and wildlife

populations and characterization of heterogeneous populations of B. burgdorferi in nature and Lyme

disease patients. The identification of a B. burgdorferi subtype that is more frequently associated with

disseminated infection in early Lyme disease patients. Presently, functional genomic approaches are being

employed to identify genes and proteins that are involved in B. burgdorferi pathogenesis.

Comparative and Functional Genomics of Borrelia burgdorferi pathogenesis.

We have determined the genetic diversity among clinical isolates of B. burgdorferi and shown that

spirochete dissemination varies significantly in patients infected with distinct genotypes. These results

demonstrate that different genotypes of B. burgdorferi possess varying potential for dissemination in an

infected host. We are employing functional and comparative genomic strategies to elucidate possible

differences in gene/protein expression between B. burgdorferi strains with differing capacities for

hematogenous dissemination. Toward this end, we have developed a whole genome array for global

expression profiling of B. burgdorferi. The expression of genes identified by these analyses will be

monitored in Lyme disease patients and infected mice and their roles in pathogenesis will be examined by

genetic manipulation. The long-term objective of this project is elucidation of genes and/or proteins that

mediate B. burgdorferi virulence.

Host Gene Expression and Lyme Disease Diagnosis.

Currently, Lyme disease diagnosis is based on both clinical findings and serologic testing. The most

commonly employed assays suffer from lack of sensitivity, standardization and a high false-positivity

rate. As a result, patients are often tested multiple times and the tendency for over testing and over

diagnosis (or misdiagnosis) is great. A long-term goal of this project is development of a novel diagnostic

approach based on alterations in host (human) gene expression induced by exposure to B. burgdorferi.

Host global gene expression, reflecting responses of the host to a specific pathogen, may have the

potential to provide evidence of such an infection. We hypothesize that B. burgdorferi infection induces

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modifications in host gene expression. Using differential gene expression analysis, we hope to identify

host genes whose expression is altered by B. burgdorferi infection. This gene set can then be employed as

an indicator for B. burgdorferi infection in clinical specimens. If successful, similar approaches may be

used for diagnosis of other microbial infections.

Faculty Member: Jan Geliebter, PhD Laboratory Location: BSB-311

Ongoing Research:

Biomarkers for Papillary Thyroid Cancer

The incidence of thyroid cancer has increased ~84% over the last decade, and mortality due to the disease

has increased ~33% over the same interval. Thus, thyroid cancer is the most common endocrine

malignancy in America. It is estimated that between 4 and 7 percent of the US population have palpable

thyroid nodules, yet only about 5% of patients with palpable nodules have thyroid cancer. Thus, the

financial and social burdens of “unnecessary” FNA biopsies are enormous. There are no serum

biomarkers for the diagnosis of papillary thyroid cancer (PTC) (~85% of thyroid cancers). Further, there

are no biomarkers that may predict which PTC will become highly invasive and would require early

vigorous intervention such as surgery with adjuvant radiation therapy. Thus there is a critical need for the

increased sensitivity and specificity in the detection, diagnosis, staging, monitoring and prognosis of

PTC. We have used high-density Affymetrix oligonucleotide arrays to analyze the gene expression

profile of 7 papillary thyroid carcinoma samples compared to 7 paired normal samples and found

significantly altered expression of 177 genes. Biologically functional clusters include transporters,

receptors, proteolysis and peptidolysis, metabolism, cell adhesion and extracellular matrix, and DNA

binding/transcription factors, among others. Real-time RT-PCR and western blots validated microarray

data for a selected set of genes and proteins. We propose to expand our analysis of potential biomarkers

to additional genes/proteins and extend our patient base to determine the level of expression of these

molecules in cancerous vs. normal tissue and in serum. We will develop PTC biomarkers with the long

term goal of linking these biomarkers with one or more of the following clinical parameters: disease

presence, progression, prognosis, alterations in stage, response to therapy and overall survival. We

propose to thoroughly analyze PTC expression of a group of biomarkers using quantitative PCR, western

blotting and immunohistochemistry. Further, we will analyze serum levels of potential PTC biomarkers

using ELISA technology. Results from this proposed study may identify biomarkers (or combinations

of biomarkers) that may be used in the diagnosis and prognosis of thyroid cancer.

Prostate Cancer

Prostate cancer (CaP) is the most common malignancy of men in America, with no curative treatment for

metastatic disease. It is estimated that over 230,000 American men will be diagnosed with CaP in the

year 2004 and 29,900 deaths will be attributed to the disease. In addition to the aging process, CaP is

thought to result from the interplay of genetic, hormonal, dietary and environmental factors. Further, in

utero exposure to elevated levels of hormones, fats and other environmental and biological “carcinogens”

are thought to predispose or imprint the prostate to an elevated level of risk for the development of cancer

later in life. Recently, the method of food preparation has come under scrutiny as a significant variable in

the etiology of cancer. Heterocyclic amines produced during the grilling of meats have emerged as major

food carcinogens and important etiologic factors in CaP. PhIP (2-amino-1-methyl-6- phenylimidazol[4,5-

b]pyridine) is the predominant heterocyclic amine in cooked meat and fish, wine, beer and cigarette

smoke. The ACI rat is an established rat model for spontaneous, naturally occurring, age-associated CaP.

PhIP induces CaP in ACI rats at a higher incidence, and earlier in life, than control rats. In utero and

perinatal exposure of rats to PhIP has been demonstrated to increase the lifelong risk of breast and colon

cancer, but has not been investigated for CaP. We propose to feed pregnant and lactating ACI rats a diet

containing PhIP and perform structural, histological and gene expression (microarray) analyses on

prostates of male pups to detect effects of PhIP on the developing prostate. Structural studies will include

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3-D reconstruction analyses will be performed on day 21 fetuses. We will also determine the lifelong risk

of CaP due to fetal/perinatal exposure to PhIP as well as alterations in gene expression. The completion

of these experiments will contribute to our understanding of the role of fetal/perinatal exposure to PhIP in

the etiology of CaP enable us to identify target molecules for intervention and design rational strategies

for the prevention of CaP.

Faculty Member: Carl V. Hamby, Ph.D. Laboratory Location: BSB-314

Ongoing Research:

EGF and VEGF-receptor mediated therapy of glioma and other brain tumors.

Project funded through the Maria Fareri Research Scholars program to evaluate cytotoxins targeting EGF

and VEGF receptors for therapy of human glioma. Tumor models for evaluating cytotoxin therapy

include smo/smo mouse model of medulloblastoma and bioluminescent monitoring of human glioma

tumors established in nude or SCID mice.

Endothelial precursor cell mobilization by enhanced external counterpulsation (EECP).

This project is funded by a private foundation and has as its goal to determine whether EECP of patients

with chronic coronary ischemia increases the mobilization of KDR+, AC133+, CD34+ endothelial

precursor cells from the bone marrow. An increase in this population may be clinically significant for its

potential to increase collateral circulation in the heart IgA nephropathy.

Private foundation grant to investigate the role of aberrant glycosylation of IgA1 antibodies in the

pathogenesis of IgA nephropathy.

Faculty Member: Dana Mordue, Ph.D. Laboratory Location: BSB-346

Ongoing Research:

Research activities in our laboratory are centered around the pathogenesis and cell biology of obligate

intracellular pathogens. Our primary model is the protozoal parasite Toxoplasma gondii. Toxoplasma

gondii is the causative agent of toxoplasmosis, a serious health hazard in immunocompromised

individuals including people with acquired immune deficiency syndrome (AIDS) and transplant

recipients. Although serious disease is associated with immune deficiency, the parasite chronically infects

20-50% of the world's population. T. gondii is also a model genetic system for other protozoa including

Cryptosporidium parvum, Cyclospora caytanensis and Plasmodium species. Current research projects in

our laboratory are aimed at identifying and characterizing novel parasite genes important for causing

disease. We use a multidisciplinary approach to evaluate the function of these genes including molecular

genetics, cell biology, immunology and biochemistry.

In previous studies we employed a functional genomics approach to identify insertional mutations that

inhibited the ability of T. gondii to cause disease but did not effect its survival in cultured fibroblasts. A

subset of these mutations also affected the ability of the parasite to survive in cells of the innate immune

system including macrophages. Our hypothesis is that this subset of parasite genes may be important for

T.gondii dissemination to the CNS in monocytes and dendritic cells during infection. Current projects

involve identification of the wild type genes disrupted by the mutations and confirming their role in

parasite pathogenesis. Identification of the genes will lead to studies evaluating the function of the

encoded proteins in infected cells and delineating their contribution to parasite pathogenesis and to acute

and chronic forms of toxoplasmosis. The long term objective of these studies is to use these parasite

proteins to begin to dissect molecular pathways important for protozoal parasites to cause disease and

evade elimination by the host immune response.

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Faculty Member: Mary Petzke, PhD. Laboratory Location: BSB-306

Ongoing Research:

Research in my lab investigates the host-pathogen interface between the mammalian immune system and

Borrelia burgdorferi, an extracellular spirochete which is the cause of Lyme disease in North America.

Our studies employ murine infection models, human blood cells from healthy donors, and skin and blood

samples from Lyme disease patients. One major line of investigation focuses on the responses of innate

immune cells to various clinical isolates of B. burgdorferi. Our objective is to uncover mechanisms of

immune evasion which enable some isolates to disseminate from the site of primary infection in the skin

to distal target tissues, causing symptoms such as arthritis, neuroborreliosis and carditis. These studies

involve approaches and techniques which encompass the fields of immunology, microbiology and

molecular biology, including the use of Green Fluorescent Protein-tagged spirochetes to quantitate and

visualize bacterial association with specific immune cell populations. Our lab was the first to

demonstrate that B. burgdorferi induces the expression of IFN-alpha, a type I IFN, by human immune

cells in a phagocytosis- and toll-like 7 and 9 receptor-dependent manner. We have recently found that

IFN-alpha and IFN-lambda, both of which classically have been associated with the response to viruses

and intracellular bacteria, are produced by human immune cells at significantly higher levels in response

to disseminating isolates versus isolates which lack the capacity to disseminate. We are expanding on this

finding by identifying the mechanism involved and have recently discovered that a single linear plasmid

of B. burgdorferi may encode a factor mediating phagocytic uptake by plasmacytoid dendritic cells and

CD14+CD11c+ cells, leading to the expression of IFN-alpha.

A second line of investigation aims to identify a unique transcriptional expression profile present in the

white blood cells of Lyme disease patients. This transcriptional fingerprint would consist of a set of

genes which are induced or suppressed in patients with active, culture-confirmed infection relative to

healthy donors. In addition to assessing mRNA expression through the use of full-genome arrays, we are

employing next-generation deep sequencing of RNA (RNA-seq) to identify mRNA splice variants and to

profile the expression of microRNAs in Lyme disease patients. Preliminary studies using human

peripheral blood mononuclear cells from healthy donors which were co-incubated ex vivo with B.

burgdorferi, Escherichia coli or Staphylococcus aureus (both common blood-borne bacterial pathogens)

revealed distinct mRNA and microRNA expression patterns. By shifting the diagnostic paradigm from

antibody-based methods to gene expression profiling, we expect to overcome many of the problems

associated with serology, including the inability to accurately diagnose very early infection as well as to

discriminate between patients with active infection and convalescent patients who have been successfully

treated with antibiotics but who will still retain circulating antibodies and memory B cells.

Faculty Member: Ira Schwartz, PhD. Laboratory Location: BSB-328

Ongoing Research:

Research activities in our laboratory focus on emerging tick-borne infectious diseases, primarily Lyme

disease and human granulocytic ehrlichiosis. Lyme disease is the most common tick-borne disease in the

United States and is caused by infection with the spirochete, Borrelia burgdorferi. Projects include

genomic approaches to elucidating the mechanisms of B. burgdorferi pathogenesis, development of

molecular diagnostics for these diseases, determination of pathogen prevalence in natural tick and wildlife

populations and characterization of heterogeneous populations of B. burgdorferi in nature and Lyme

disease patients. the identification of a B. burgdorferi subtype that is more frequently associated with

disseminated infection in early Lyme disease patients. Presently, functional genomic approaches are

being employed to identify genes and proteins that are involved in B. burgdorferi pathogenesis.

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Comparative and Functional Genomics of Borrelia burgdorferi pathogenesis.

We have determined the genetic diversity among clinical isolates of B. burgdorferi and shown that

spirochete dissemination varies significantly in patients infected with distinct genotypes. These results

demonstrate that different genotypes of B. burgdorferi possess varying potential for dissemination in an

infected host. We are employing functional and comparative genomic strategies to elucidate possible

differences in gene/protein expression between B. burgdorferi strains with differing capacities for

hematogenous dissemination. Toward this end, we have developed a whole genome array for global

expression profiling of B. burgdorferi. The expression of genes identified by these analyses will be

monitored in Lyme disease patients and infected mice and their roles in pathogenesis will be examined by

genetic manipulation. The long-term objective of this project is elucidation of genes and/or proteins that

mediate B. burgdorferi virulence.

Host Gene Expression and Lyme Disease Diagnosis.

Currently, Lyme disease diagnosis is based on both clinical findings and serologic testing. The most

commonly employed assays suffer from lack of sensitivity, standardization and a high false- positivity

rate. As a result, patients are often tested multiple times and the tendency for over testing and over

diagnosis (or misdiagnosis) is great. A long-term goal of this project is development of a novel diagnostic

approach based on alterations in host (human) gene expression induced by exposure to B. burgdorferi.

Host global gene expression, reflecting responses of the host to a specific pathogen, may have the

potential to provide evidence of such an infection. We hypothesize that B. burgdorferi infection induces

modifications in host gene expression. Using differential gene expression analysis, we hope to identify

host genes whose expression is altered by B. burgdorferi infection. This gene set can then be employed as

an indicator for B. burgdorferi infection in clinical specimens. If successful, similar approaches may be

used for diagnosis of other microbial infections.

Faculty Member: Raj K. Tiwari , Ph.D. Laboratory Location: BSB-331

Ongoing Research:

The objective of the laboratory is to design and test cancer vaccines with experimental models in prostate,

breast and thyroid cancer. Vaccines being developed are synthetic peptides based on their ability to

mimic cancer antigens. Molecular mechanism of chemopreventive and therapeutic agents with a view to

use cellular pathways to improve cancer therapy and prevent progression of disease are being actively

examined.

Some specific examples of ongoing projects are:

Identification of prostate cancer specific heat shock proteins and peptide mimics that can induce a

specific immune response in prostate cancer. This involves purification of cancer specific heat shock

proteins and the interaction of these purified proteins with immune repertoire of antibodies that are

constructed in vitro using molecular biological techniques such as phage display synthetic

combinatorial antibody libraries Examining the molecular targets of a dietary chemical present in cruciferous vegetables on the

prevention of prostate, breast and thyroid cancer. These studies the interaction of these agents on cell

growth regulating pathways and cell signaling pathways

Examining the molecular target of a new chemotherapeutic drug that has specificity toward prostatecancer. This involves determining maximum tolerable doses in cancer cell and animal models andexamining the basis of its molecular action by gene array analysis

Determination of prognostic markers in thyroid cancer and the genetic changes that are necessary

and sufficient for goiter, thyroid nodules, papillary and follicular thyroid cancer.

All of the projects are applicative and utilize basic science research as it can be translated to human

patients for prevention of progression and therapy of prostate, breast and thyroid cancer.

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PATHOLOGY

Faculty Member: Zbigniew Darzynkiewicz, MD, PhD Laboratory Location: BSB-439

Ongoing Research:

Current research activity concentrates on cancer cell growth and the regulatory mechanisms associated

with cell proliferation, apoptosis and sensitivity to anti-tumor drugs. New methods were developed and

applied to assess induction of DNA damage by antitumor drugs and other genotoxic agents, and correlate

extent of the damage with initiation of apoptosis in relation to the cell cycle phase. Studies are also

ongoing on DNA damage by endogenous oxidants generated during metabolism in relation to cell aging

and senescence.

Faculty Member: Dumitru A. Iacobas, PhD Laboratory Location: BSB-410

Ongoing Research:

For possible projects please see description of the Systems Biology Core Laboratory:

http://www.nymc.edu/Research/CoreFacilitiesAndResources/SystemsBiologyCore.html

Faculty Member: Michael J. Iatropoulos, MD, PhD Laboratory Location: BSB-430

Ongoing Research:

Developing methodology for testing of chemicals and physical agents to assess potential carcinogenic

activity and human cancer hazard. Monitoring of early events of carcinogenesis such as DNA adducts,

cytotoxicity, enzyme transformation, cell apoptosis and cell proliferation.

Faculty Member: Paul A. Lucas, PhD Laboratory Location:

Ongoing Research:

The laboratory is focused on regenerative medicine, or tissue engineering, using adult stem cells. There

are two general areas of research: 1) characterization of the stem cells and determination of their ability

to differentiate into different phenotypes and 2) use of the stem cells to regenerate tissues/organs. The

former involves stem cells isolated from adult humans and the latter involves animal models of

regeneration (with allogenic adult stem cells from the appropriate species).

We are currently characterizing the stem cells by identifying cell surface markers on the stem cells and

comparing that profile with other adult stem cells, evaluating the ability of the stem cells to differentiate

into retinal cells, nucleous palposus chrondrocytes, and endodermal phenotypes such as hepatocytes and

pancreatic islet cells, and testing whether cancer cell lines have differentiation capabilities and markers

similar to the adult stem cells.

We have shown that the adult stem cells apparently respond to local cues to differentiate into the

phenotypes at the site of implantation. Placement of undifferentiated adult stem cells into regeneration

models for articular cartilage, meniscus, bone (calvaria), and mesothelium (abdominal adhesions) have

resulted in the formation of the appropriate tissue(s). This simplifies the use of the stem cells in

regeneration because we do not have to pre-differentiate the stem cells to specific phenotypes in vitro. In

the coming year, we are conducting or planning experiments to use the stem cells for regeneration of

defects in rat femur, rabbit intervertebral disc, and mouse kidney. Regeneration will be assessed by

histology (restoration of morphology) and assays for functionality – mechanical strength for femur and

disc and creatinine clearance for kidney.

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Faculty Member: Caroline Ojaimi, PhD Laboratory Location: BSB-639

Ongoing Research:

The interest of Dr. Ojaimi is to use gene array technology as well as functional genomic approaches in vascular biology. In particular, Dr. Ojaimi interest is to explore difference in gene expression of normal

and diseased heart in a number of animal models. Emphasis is on identifying pathways of gene regulation

which may be responsible for the altered expression of eNOS and other functionally related enzymes.

Functional genomic approach will be used to elucidate the critical role played by eNOS associated

molecular alterations in heart failure and in different metabolic diseases which lead to cardiovascular

dysfunction.

Faculty Member: Frank Traganos, Ph.D. Laboratory Location: BSB-438

Ongoing Research:

Understanding the interaction between the various activating and inactivating events of cell proliferation

is important since it is many of these molecules (e.g., the product of the retinoblastoma gene, pRb; p53;

p21; cyclin-dependent kinases and their activating cyclins, etc.) which are modified in cancer cells either

because they are mutated, deleted or over-expressed. Utilizing sophisticated, multiparameter flow

cytometric analyses, it is possible to examine the expression of the various molecules in individual cells

at rates of 100s of cells/second. Since several (up to 7) attributes of each cell can be determined

simultaneously it is possible to perturb the cells by affecting their ability to proliferate and examine how

such perturbations affect cell cycle progression in normal and tumor cells, respectively. Insights gained

regarding these control mechanisms not only provide additional information on how the mechanisms

controlling cell proliferation operate, they also provide targets for intervention in cancer as well as values

which may be useful in diagnosis, determining patient prognosis and/or response to therapy.

Loss of control of cell proliferation is not the only change observed in tumor cells. Tumor cells also

require some mechanism which circumvents the normal signals which lead to cell death or apoptosis and

provide a degree of immortality. Here as well, understanding the controls which operated in the various

signaling pathways which lead to apoptosis helps us understand how the pathways are circumvented in

cancer.

In addition to studies of cell proliferation and apoptosis, work is now in progress to detail the events that

are involved in DNA damage repair. A histone variant, histone H2AX which is involved in packaging

DNA into nucleosomes is also phosphorylated at the site of DNA double- strand breaks (DSBs) as might

arise from a cell’s interaction with radiation, many chemotherapeutic agents or a host of compounds that

induce reactive oxygen species within cells. Utilizing probes to this histone modification it is possible to

detect substances that cause DNA DSBs, the kinetics of formation of DSBs and the kind of molecular

species involved. Work is in progress to identify the sequence of activation of several of the other

molecules involved in the process including the ataxia telangiectasia mutated gene product (ATM) which

is the kinase that phosphorylates H2AX at, and surrounding, the break sites. The activation of ATM (it is

phosphorylated on serine 1981) relative to the recruitment and/or activation of other DNA repair proteins

is an area of intense research interest and little is known about how these molecules behave in situ.

Research on the phosphorylated H2AX has also revealed that there is a constitutive level of this form of

histone in normal cells presumably arising as a result of the cell’s metabolic activity that inevitably leads

to generation of reactive oxygen species. Experiments have demonstrated that this basal level of

hosphorylated H2AX can be diminished by treatment with scavengers of oxygen free radicals. It may

well be that the ongoing repair of such damage is associated with the aging process since double strand

break repair is often imperfect. Studies of ways of lowering constitutive levels of phosphorylated H2AX

may uncover molecules that slow the aging process.

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Faculty Member: Gary M. Williams, MD Laboratory Location: BSB-438

Ongoing Research:

We are investigating the molecular and cellular events in the process of chemical carcinogenesis in rat

liver. Our particular focus is on the nature of genetic changes critical to the process. Related to this, we

are also studying interventions to inhibit the process of chemical carcinogenesis.

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PHARMACOLOGY

Faculty Member: Mairead A. Carroll, PhD Laboratory Location: BSB-541

Ongoing Research:

Our research projects are focused in the area of cardiovascular disease, in particular, we study the role of

the kidneys in regulating blood pressure. The complex control mechanisms governing this renal function

are orchestrated within the preglomerular microvessels (PGMV) which maintain a constant renal blood

flow and glomerular filtration rate by adjusting their resistance in response to perfusion pressure

fluctuations, i.e. autoregulation. For over two decades we have been studying the function of a class of

renal lipids derived from arachidonic acid known as cytochrome P450 (CYP)-derived eicosanoids (CYP-

AA) and have shown that this pathway plays an important role in salt and water excretion and, therefore,

in the regulation of extracellular fluid volume and blood pressure control. The major CYP-AA

metabolites, 20-hydroxyeicosatetraenoic acids (20- HETE) and four regioisomeric cis-

epoxyeicosatrienoic acids (EETs), 5, 6-, 8, 9-, 11, 12- and 14, 15-EETs, generated by hydroxylases and

epoxygenases, respectively, occupy a key position in the regulation of renal function. The constrictor

effect of 20-HETE on PGMV established its importance in mediating tubuloglomerular feedback (TGF)

and renal auto regulation. In contrast, EETs, prime candidates for endothelium-derived hyperpolarizing

factors, exhibit dilator activity on the renal vasculature of rats by increasing the open-state probability of

calcium-dependent potassium channels of vascular smooth muscle cells and inhibit sodium reabsorption.

Adenosine, a metabolite of ATP, modulates cellular and organ function by binding to specific cell-surface

P1 purinergic receptors, of which there are four known subtypes (A1, A2A, A2B and A3. The

physiological effects of adenosine are observed in nearly every tissue and organ and are expressed in

PGMV. In the kidney, activation of adenosine1 receptors (A1 R) and A2 R participate in the regulation

of renal vascular tone and tubular function. Stimulation of A1 R constricts the renal vasculature,

decreases TGF, inhibits renin release and enhances proximal tubular NaCl reabsorption, whereas

stimulation of A2A R increases renal blood flow, and reduces NaCl reabsorption and decreases blood

pressure.

We have shown that the A2AR selective agonist, CGS 21680, stimulates EET release, without affecting

20-HETE levels, from rat PGMV and that the vasodilator action of CGS 21680 in arcuate arteries is

inhibited by a selective epoxygenase inhibitor. Further, the 11, 12-EET is the most likely candidate for

mediating arcuate arterial dilation in response to activating A2A R with CGS 21680. As EETs are

vasodilators and natriuretic and can account for the biological actions of adenosine acting on A2AR, we

suggest an interdependency involving the purinergic system and CYP-derived AA metabolites in renal

microcirculatory regulation and propose 1) that the EETs are mediators / messengers of the biological

functions of adenosine acting via A2AR and 2) this signaling pathway via A2AR/EETs is involved in the

adaptive response to increased dietary salt intake.

Activation of A2AR and stimulation of EET levels of PGMV can affect major indices of renal function:

renal vascular resistance, renal interstitial pressure, and medullary blood flow. These effects may

influence sodium reabsorption by altering peritubular pressure and tubular fluid volume and flow, thereby

promoting natriuresis. Since the tone and reactivity of PGMV are key components in renal auto

regulation and TGF, A2AR activation can also serve in mechanisms that contribute to the regulation of

blood pressure. Selective A2A R agonists may provide a novel therapeutic approach to controlling blood

pressure.

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Faculty Member: Nicholas R. Ferreri, Ph.D. Laboratory Location: BSB-505

Ongoing Research:

Mechanisms that regulate salt and water transport in the kidney are critical to understanding the

development of hypertension. Accordingly, the laboratory is uncovering features of a cytokine-based

mechanism that interacts with eicosanoids to control sodium and chloride reabsorption in the medullary

thick ascending limb of Henle (mTAL), a nephron segment that reabsorbs 25% of filtered NaCl and is the

site of action of ‘loop’ diuretics. We investigate the role of tumor necrosis factor-alpha (TNF) in the

context of cardiovascular disease and renal function using a combination of: 1) in vivo models in which

genetic deletion of components of the TNF system are used to determine their effects on blood pressure

and sodium excretion, and 2) in vitro cellular and molecular models based on cultures of mTAL cells that

allow for a direct assessment of TNF components on the activity and expression of ion transport pathways

and the regulation of the nuclear factor of activated T cell (NFAT) family of transcription factors that

regulate TNF production in these cells. We have demonstrated that the effects of TNF on blood pressure

and sodium excretion are differentially regulated by two distinct TNF receptors and suggest that

uncoupling of this mechanism could contribute to inappropriate responses to activation of blood pressure

elevating hormonal systems. Moreover, inhibition of NFAT-mediated TNF gene transcription, which is

critical to the regulation of salt and water homeostasis and subject to short- and long-term regulation via

different monooxygenases, may contribute to the nephrotoxic effects of immunosuppressive agents such

as cyclosporine A.

Faculty Member: Austin Meng Guo, PhD. Laboratory Location: BSB-546A

Ongoing Research:

My research interests are focused on the role of Cytochrome P450 derived eicasonoids, specifically 20-

hydroxyeicosatetraenoic acid (20-HETE), in the regulation of angiogenesis and cancer growth. Abnormal

neovascularization is associated with many serious human diseases, i.e. ischemia and cancer. Recent

developments in stem cell biology suggest that circulating endothelial precursor cells (EPC) contribute to

postnatal neovascularization, which is an important adaptation for recovery from critical ischemia. Since

EPC-induced neovascularization appears essential for repair of ischemic tissue, it is crucial that we

understand the factors that regulate EPC involvement in the neovascularization process. We have shown

that the 20-HETE and its synthases (CYP4A and F family of enzymes in human) regulate endothelial

progenitor cell functions such as proliferation, migration, and angiogenic gene expression. Inhibition of

20- HETE synthesis abrogated EPC proliferation and migration towards vascular endothelium growth

factor (VEGF) and stroma-derived factor 1 (SDF-1) in vitro. VEGF and SDF-1 are two of the most

important regulators of EPC involvement in the angiogenic process. Thus, the CYP4A-20- HETE system

may be a key to the regulation of the angiogenic and homing functions of EPC in response to ischemia.

Stemming from our studies in the role of the CYP4A/F-20-HETE system in regulation of angiogenic

processes, we are also interested in the regulation of cancer growth by the CYP4A/F- 20-HETE system.

Pharmacological inhibitors of 20-HETE synthases and 20-HETE antagonists have been shown to

decrease the growth of some cancers both in vitro and in vivo suggesting the CYP4A/F-20-HETE system

may be a novel target for treating some cancers.

Faculty Member: Houli Jiang, MD Laboratory Location: BSB-546A

Ongoing Research:

Our current research is focusing on a new mechanism of activating cytochrome P450 metabolism that

transforms arachidonic acid to cis- and trans-epoxyeicosatrienoic acids (EETs) vasodilatory, anti-

inflammatory and antihypertensive lipid mediators. P450s have major impacts on human physiology by

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producing regio- and stereo-selective oxygenations of organic substrates. P450 metabolism is usually

started by NADPH providing electrons to flavins in the reductase that transfers electrons to P450s

resulting in substrate monooxygenation. While a 1:1 functional complex of P450 and reductase is needed

for a P450 reaction cycle, P450 is in excess by 10 to 20-fold over the reductase in microsomes. We have

found that EETs can be generated by a novel P450 activation that bypasses the requirement of NADPH.

Production of vasoactive lipid mediators, such as EETs and 20-HETE, are modulated in our research that

is potentially significant for vascular protection, blood pressure regulation and treatment of other

cardiovascular diseases.

Faculty Member: Mario A. Inchiosa, Jr., Ph.D. Laboratory Location: BSB-548

Ongoing Research:

Mario A. Inchiosa, Jr., professor, conducts much of his research in collaboration with the Department of

Anesthesiology. His lab is investigating reflex sympathetic dystrophy, a condition also known as complex

regional pain syndrome, which sometimes occurs in patients following apparent full recovery from

trauma or surgery to the hand, wrist, foot or ankle. His hypothesis is that in some patients, sensory

pathways that conduct pain perception have become exaggerated or “supersensitive,” a condition

believed to be induced by catecholamines (epinephrine and norepinephrine). Dr. Inchiosa and his

colleagues have tested the clinical effects of the drug, phenoxybenzamine, a little used antihypertensive

drug that can produce a long-term block of some of the effects of catecholamines. The research is

designed to discover ways of reversing the supersensitive state that causes the very painful syndrome. A

second area of research involves the development of sensitive point-of-care assays to evaluate the

competence of hemostatic mechanism in human blood.

Faculty Member: Daohong Lin, MD Laboratory Location: BSB-538

Ongoing Research:

The ROMK channel is a member of Kir and responsible for K secretion in the apical membrane of

connecting tubule (CNT) and cortical collecting duct (CCD). High dietary potassium intake enhances K+

secretion by stimulating the surface expression of ROMK channels in the aldosterone-sensitive distal

nephron (ASDN), but the mechanism by which this occurs is incompletely understood. We have found

that high-potassium diet increases the transcription of miR-802 in the cortical collecting duct in mice. In

addition, the expression of caveolin-1, whose 3′untranslated region (3’ UTR) contains the seed sequence

of miR-802, is down-regulated. The expression of miR-802 could suppress the expression of caveolin-1,

and conversely, the down regulation of endogenous miR-802 increases the expression of caveolin-1 in

HEK cells. MiR-802 mediates the stimulatory effect of a high-potassium diet on ROMK channel activity

by suppressing caveolin-1 expression, which leads to the increased surface expression of ROMK

channels in the distal nephron.

WNKs (With-no-lysine kinase)are serine/threonine protein kinases and WNK1, 3 and 4 are expressed in

the CCD. A large body of evidence indicates that the WNK family plays an important role in the

regulation of ROMK channels. Expression of WNK4 inhibits the ROMK channel activity and such effect

could be abolished by the stimulation of c-Src activity.

Faculty Member: Alberto Nasjletti, MD Laboratory Location: BSB-525

Ongoing Research:

Research activities in my laboratory are concerned with the investigation of the role played by

cytochrome P450 2E1 (CYP2E1)-derived eicosanoids in the regulation of vasoconstrictor responsiveness

and blood pressure in rats and mice. We focus on CYP2E1-dependent vascular production of 19(R)- and

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18(R)-hydroxyeicosatetraenoic acids (HETE), the vasoregulatory action of such eicosanoids and their

interaction with 20-HETE, and the notion that 19(R)- and 18(R)- HETE subserve antihypertensive

functions by interfering with 20-HETE-induced sensitization of vascular smooth muscle to constrictor

stimuli. The following aims will be addressed:

AIM 1: To test the hypothesis that high blood pressure elicits reduction of vascular CYP2E1 andsynthesis of 19(R)- and 18(R)-HETE, with attendant amplification of 20- HETE-induced sensitizationto constrictor stimuli, bringing about augmentation of vascular reactivity. Studies will be conductedin SHR, in rats made hypertensive by treatment with deoxycorticosterone or angiotensin II, and innormotensive controls. We seek to determine relationships between the level of blood pressure,vascular CYP2E1 expression and reactivity to constrictor stimuli as affected by 20-HETE andCYP2E1-derived eicosanoids.

AIM 2: To test the hypothesis that gender, dietary potassium and dietary sodium influence vascular

CYP2E1 expression and synthesis of 19(R)- and 18(R)-HETE, with consequential alterations in

constrictor responsiveness resulting from changes in the effectiveness of the 20-HETE-dependent

mechanism of vascular sensitization to constrictor stimuli. We will explore relationships between

vascular CYP4A and CYP2E1 expression, synthesis of 20-, 19(R)- and 18(R)-HETE, and

responsiveness to constrictor stimuli as a function of gender and dietary potassium and sodium.

AIM 3: To test the hypothesis that up regulation of vascular CYP2E1 expression and synthesis of

19(R)- and 18(R)-HETE attenuates the development of hypertension. The effects of CYP2E1 gene

transfer on blood pressure, vascular CYP2E1 and synthesis of CYP-derived eicosanoids, and

reactivity of the vasculature to constrictor stimuli will be explored in SHR, and rats made

hypertensive by angiotensin II infusion or injection of an adenoviral construct expressing CYP4A2.

AIM 4: To test the hypothesis that reduction of vascular CYP2E1 activity and/or expressionpromotes elevation of blood pressure. We seek to determine whether blood pressure and bloodpressure responsiveness to angiotensin II infusion are enhanced in rats undergoing inhibition of

CYP2E1, and in CYP2E1-null mice.

Faculty Member: C. Andrew Powers, PhD Laboratory Location:

Ongoing Research:

Glandular kallikrein (GK) is a trypsin-like protease classically characterized by its ability to generate

bioactive peptides (kinins) from large inactive precursor proteins (kininogens). Investigation of the

potential role of GK in prohormone processing led to its discovery in the anterior pituitary where it is

highly induced by estrogens and repressed by dopamine in lactotrophs - cells that secrete prolactin (PRL).

A novel thiol-dependent processing reaction was discovered which enabled GK to cleave 3 highly

conserved sites in the C-terminus of PRL to generate a large N-terminal fragment (174 a.a.), and 3

smaller peptides (11, 3, and 9 a.a.). The pituitary was found to secrete a novel estrogen- and thiol-

dependent PRL product (PRL1-173) produced via serial processing by GK and carboxypeptidase E. The

biological significance of this highly regulated and unusual processing remains a mystery.

Further research focuses on the integrative physiological mechanisms contributing to the effects of

estrogens and antiestrogens (such as tamoxifen) on energy balance, bone and lipid metabolism, growth

and cardiovascular function in rat models relevant to human physiology and pathophysiology. The work

indicates that estrogen and antiestrogen modulation of the actions and/or secretion of thyroid hormone,

growth hormone (GH) and insulin-like growth factor I (IGF-I) contributes to estrogen and tamoxifen

effects on a diverse subset of estrogen targets.

Conversely, changes in the functional status of the thyroid or GH-IGF-I axis may alter the effects of

estrogens and antiestrogens on such targets. The research clarifies the factors contributing to estrogen and

antiestrogen actions on differing targets, and may provide insights relevant to the development of novel

therapeutic uses for antiestrogens.

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Faculty Member: Michal L. Schwartzman, PhD Laboratory Location: BSB-530

Ongoing Research:

Cytochrome P450 eicosanoids in Hypertension We have shown a correlation between the production of a renal cytochrome P450 (CYP) arachidonate

metabolite, namely, 20-hydroxyeicosatetraenoic acid (20-HETE), and the development of hypertension in

genetic and experimental animal models. We also showed association between urinary 20-HETE

excretion and salt-sensitive hypertension in human. In recent years, we identified 20-HETE as the

mediator of androgen-dependent hypertension. Hypertension is a disease that can lead to many

manifestations including strokes, heart attacks, and renal failure. It is recognized that men are at greater

risks for hypertension than women and that androgen plays an important role. The cellular mechanism

underlying the androgen-induced increase in blood pressure and susceptibility to cardiovascular

morbidity is not completely known. Studies are aimed at understanding 20-HETE cellular and molecular

mechanisms of action with the goal of uncovering novel therapeutic targets for the treatment of

hypertension driven by increased androgen levels that not only occur in men but is also believed to

underlie the increased susceptibility to hypertension in menopausal women. The experimental approach

is multi-faceted and includes the use of transgenic mice and genetically modified rats as well as

molecular and pharmacological probes together with cell culture models.

Ocular surface inflammation and neovascularization

We have shown that injury to the ocular surface provokes inflammatory and angiogenic response that is

mediated by corneal epithelial-derived lipid mediators generated by a cytochrome P450 monooxygnease,

identified as CYP4B1. These lipid mediators exhibit potent inflammatory and angiogenic properties.

Studies in the lab are directed towards:

elucidation of the cellular and molecular mechanisms underlying the inflammatory and angiogenic

activity of these metabolites including receptor identification, activation of nuclear factors and

induction of gene expression

determination of the consequence of CYP4B1 overexpression and suppression by genetic

manipulation on ocular surface inflammation and corneal neovascularization in experimental models

identification of anti-inflammatory and cytoprotective pathways (i.e., heme oxygenases, HO-1 and

HO-2) that control the action of CYP4B1-derived inflammatory and angiogenic eicosanoids using

targeted gene deletion (knockout mice) and gene overexpression

identification of molecular and cellular mechanisms responsible for the cytoprotective and anti-

inflammatory properties of the HO system. These studies would determine the functional implication

of this pathway and its metabolites in pathophysiological processes specifically corneal

neovascularization, a major problem in clinical ophthalmology in various conditions such as corneal

transplantation, contact lens wear, trachoma and other infectious conditions.

Faculty Member: Charles T. Stier, Jr., Ph.D. Laboratory Location: BSB-508

Ongoing Research:

It is well-known that high-salt intake can be a causative factor in blood pressure elevation. However, little

is known about how high salt-intake can sensitize to end-organ damage (stroke, myocardial infarction and

renal dysfunction). Our previous data, indicate that high blood pressure alone may not be sufficient to

provoke vascular injury in our stroke-prone spontaneously hypertensive rat (SHRSP) model of end-organ

damage. Recent evidence had linked epoxyeicosatrienoic acids (EETs) to the prevention of end-organ

damage and high-salt intake to the release of EETs. Our recently published studies and preliminary data

indicate a strong connection between EETs and prevention of salt-sensitive end-organ damage in SHRSP.

These studies will provide information relevant to the development of clinical therapeutic interventions to

combat end-organ damage beyond that of lowering blood pressure.

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The metabolic syndrome is a condition characterized by elevated blood pressure, obesity,

hypertriglyceridemia, and insulin insensitivity. The metabolic syndrome has also been referred to as

syndrome X. Patients with the metabolic syndrome thus display multiple derangements which feature not

only hypertension but also diabetes and hyperlipoproteinemia. One of the obstacles to the study of the

metabolic syndrome has been the availability of an animal model which possesses all the phenotypic

changes that are present clinically. One model is the obese spontaneously hypertensive rat (SHROB)

which was original developed by Dr. Koletsky. These animals are now commercially available from

Charles River Laboratories. In planned studies, we will more fully characterize the chronological

development of the metabolic syndrome phenotype in these rats. Our goal is to establish this animal

model for future studies to investigate to agents such as niacin, and niacin-like compounds, which have a

profile of activities that should result in prevention or reversal of the metabolic syndrome.

Faculty Member: Wen-Hui Wang, MD Laboratory Location: BSB 537-8, C04

Ongoing Research:

Na is a major extracellular ion and plays a key role in maintaining extracellular volume. Decreasing

extracellular Na content can result in hypotension whereas increasing Na content causes hypertension.

Under normal condition extracellular Na content is well balanced and kidney plays a key role in

maintaining Na metabolism: high Na intake suppresses whereas low Na intake increases Na absorption in

the distal nephron. There are many factors regulate Na transport in the kidney including aldosterone. In

addition, renal cells can also generate local factors which regulate Na transport (autocrine). We have

identified arachidonic acid metabolites of cytochrome P450 epoxygenase, CYP2C23, plays an important

role in the regulation of Na transport in the distal nephron. High Na intake stimulates CYP2C44 activity

and thus inhibits Na absorption in the distal nephron. Defective regulation of CYP2C44 can cause the

salt-sensitive hypertension. Our laboratory has used multiple methodology including molecular biology,

patch- clamp technique, metabolic cage and protein chemistry to study the role of CYP2C44 in regulating

ENaC and renal Na transport.

Another project in the last ten years is to study the renal K secretion. K is mainly located in the

intracellular fluid and extracellular K must be maintained in a normal narrow range: high plasma K

(hyperkalemia) or low plasma K (hypokalemia) can cause life-threatening cardiac arrhythmia. Disorder of

K balance (hypo or hyperkalemia) is a common syndrome in patients with kidney failure. Kidney plays a

key role in secreting K to match the dietary K intake: high K intake stimulates and low K intake decreases

K secretion. My research interest is to identify the factor which regulates K secretion.

Renal K transport involves a variety of membrane proteins such as K channels and Na-K- ATPase. We

are focused on studying the molecular mechanism by which protein kinases regulate the metabolism of

renal K channels. We have identified protein tyrosine kinase and WNK (with- no-lysine kinase) play an

important role in the regulation of renal K secretion. Also, we have use miRNA array to identify miRNA

which regulates K channels. We have identified several miRNA including miR-802, miR-192 and

miR142-3P in regulating renal K secretory channels. These studies could lead to develop new approaches

to treat K metabolism disorder.

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Faculty Department Research InterestAlmond, Gregory, MD, MPH, FACEP

Emergency Medicine Clinical Research

Alpan, Gad, MD Pediatrics (Neonatology) NeonatologyBakshi, Chandra Shekhar, DVM, PhD

Microbiology and Immunology Study of Frencisella tularensis

Ballabh, Praveen, MD Cell Biology and Anatomy Prevention of germinal matrix hemorrhage and post-hemorrhagic complication in premature infants

Ballabh, Praveen, MD Pediatrics (Neonatology) NeonatologyBanerjee, Ranjit, PhD Microbiology and Immunology Effect of Cofactors on HIV-1 Gene

Expression; Identification of Genes Controlling Lymphocytic Differentiation and Transformation; Effect of Cofactors on the interaction HIV-1 and HBV Gene Expression

Banquet, Agnes, MD Pediatrics (Pediatric Pulmonology, Allergy and Sleep Medicine)

Pediatric Pulmonology, Allergy and Sleep Medicine

Bessen, Debra, PhD Microbiology and Immunology Group A beta-hemolytic streptococci (Streptococcus pyogenes)

Bierman, Frederick, MD Pediatrics (Pediatric Cardiology) Pediatric CardiologyBoyer, Jay, MD Pediatrics (Pediatric Pulmonology,

Allergy and Sleep Medicine)Pediatric Pulmonology, Allergy and Sleep Medicine

Brumberg, Heather MD, MPH Pediatrics (Neonatology) Neonatology

Bucher, Doris, PhD Microbiology and Immunology Influenza vaccine developmentCabello, Felipe C., MD Microbiology and Immunology Ability of B. burgdorferi to produce disease in

humans and animalsCalo, Joy MD Pediatrics (Neonatology) NeonatologyCarroll, Mairead A., PhD Pharmacology Cardiovascular disease; Role of kidneys in

regulating blood pressureClare, Camille A., MD, MPH, CPE, FACOG

Obstetrics and Gynecology Clinical Research

Cooper, Arthur J.L., PhD Biochemistry and Molecular Biology Contribution of the metabolism of selenium-containing amino acids to chemoprevention

Darzynkiewicz, Zbigniew, MD, PhD

Pathology Cancer cell growth and the regulatory mechanisms associated with cell proliferation, apoptosis, and sensitivity to anti-tumor drugs

Dattwyler, Raymond, MD Microbiology and Immunology Emerging tick-born infectious diseasesde la Riva-Velasco, Elizabeth, MD

Pediatrics (Pediatric Pulmonology, Allergy and Sleep Medicine)


Dozor, Allen J., MD Pediatrics (Pediatric Pulmonology, Allergy and Sleep Medicine)


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Index of Investigators

Faculty Department Research InterestDrs. Ritch, Rittermand, Gentile, Sidoti, Della Rocca, Finger, & Samson

Opthalmology General and Speciality Opthalmology

Erb, Markus, MD Pediatrics (Pediatric Cardiology) Pediatric CardiologyEtlinger, Joseph D., PhD Cell Biology and Anatomy Regulatory proteins that associate with

proteasomes and how modification may influence protein turnover

Ferreri, Nicholas R., PhD Pharmacology HypertensionFish, Bernard G., MD Pediatrics (Pediatric Cardiology) Pediatric CardiologyFried, Victor A., PhD Cell Biology and Anatomy Posttranslational regulation and cellular states

Friedman, Deborah, MD Pediatrics (Pediatric Cardiology) Pediatric CardiologyGeliebter, Jan, PhD Microbiology and Immunology Biomarkers for Papillary Thyroid Cancer;

Prostate CancerGewitz, Michael, MD Pediatrics (Pediatric Cardiology) Pediatric CardiologyGiamelli, Joseph, MD Pediatrics (Pediatric Cardiology) Pediatric CardiologyGjonaj, Suzette, MD Pediatrics (Pediatric Pulmonology,


Gogcu, Semsa, MD Pediatrics (Neonatology) NeonatologyGoligorsky, Michael S., MD, PhD

Nephrology Endothelial Cell Dysfunction; Acute Kidney Injury

Golombek, Sergio, MD, MPH Pediatrics (Neonatology) NeonatologyGuo, Austin Meng PhD Pharmacology Regulation of angiogenesis and cancer growth

Hamby, Carl V., PhD Microbiology and Immunology EGF and VEGF-receptor mediated therapy of glioma and other brain tumors

Hannan, Frances, PhD Cell Biology and Anatomy Molecular mechanisms underlying complex processes such as learning and memory and auditory function

Herzberg, Gilbert, MD Pediatrics (Pediatric Cardiology) Pediatric CardiologyIacobas, Dumitru A., PhD PathologyIatropoulos, Michael J., MD, PhD

Pathology Developing methodology for testing of chemicals and physical agents to assess potential carcinogenic activity and human cancer hazard

Inchiosa Jr., Mario A., PhD Pharmacology Reflex Sympathetic DystrophyIssenberg, Henry, MD Pediatrics (Pediatric Cardiology) Pediatric CardiologyJain, Supriya, MD Pediatrics (Pediatric Cardiology) Pediatric CardiologyJhanwar, Meena, PhD Pathology Characterization of Cancer stem cell from

brain tumors; Mechanisms for organ-specific cancer metastasis; Analysis of the cell signaling pathways triggered by BRCA1, PTEN, p53, and RAS proteins; Understanding of promoter-specific regulation of gene

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Faculty Department Research InterestJiang, Houli, MD Pharmacology Production of vasoactive lipid mediatorsJokl, Han Hirsch-Kauffman, MD Opthalmology Retinal Diseases

Kang, Jian, MD, PhD Cell Biology and Anatomy Interplay between glial cells and neurons; Kainate receptor-mediated modulation of GABAergic synapses; Activity-dependent potentiation of intrinsic neuronal excitability

Kase, Jordan, MD Pediatrics (Neonatology) NeonatologyKim, Y. Cathy, MD Pediatrics (Pediatric Pulmonology,


Kirtok, Necla, MD Pediatrics (Neonatology) NeonatologyKocherlakota, Prabakar, MD Pediatrics (Neonatology) NeonatologyKrishnan, Sankaran, MD Pediatrics (Pediatric Pulmonology,


Kronn, David, MD Pediatrics (Medical & Biochemical Genetics)

Medical Genetics

La Gamma, Edmund F., MD Pediatrics (Neonatology) NeonatologyLee, Marietta, PhD Biochemistry and Molecular Biology Characterization and identification of the

subunits of human pol δ and its accessory proteins; Investigation of the molecular linkage between regulatory systems that control cellular DNA replication and pol δ,

Lerea, Ken, PhD Cell Biology and Anatomy The relationship between threonyl phosphorylation of the Glyprotein Iib-IIIa and microparticle formation

Levin, Aaron, MD Pediatrics (Pediatric Cardiology) Pediatric CardiologyLim-Melia, Elizabeth, MD Pediatrics (Medical & Biochemical

Genetics)Medical Genetics

Lin, Daohong, MD Pharmacology Kidney diseaseLin, Robert Y., MD General Medicine Incidence of gammaglobulin use in New York

StateLucas, Paul A., PhD Pathology Regenerative medicineLucas, Paul, PhD Orthopedic Surgery Tissue EngineeringMalhotra, Yogangi, MD Pediatrics (Neonatology) NeonatologyMathew, Rajamma, MD Pediatrics (Pediatric Cardiology) Pediatric CardiologyMercado, Myra, MD Pediatrics (Neonatology) NeonatologyMercado, Vanessa, MD Pediatrics (Neonatology) NeonatologyMiliaresis, Christa, MD Pediatrics (Pediatric Cardiology) Pediatric CardiologyMordue, Dana, PhD Microbiology and Immunology The pathogenesis and cell biology of obligate

intracellular pathogens- primarily Toxoplasma gondii

Nankova, Bistra, PhD Pediatrics (Neonatology) NeonatologyNasjletti, Alberto, MD Pharmacology Regulation of vasoconstrictor responsiveness

and blood pressure

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Faculty Department Research InterestNewman, Stuart A., PhD Cell Biology and Anatomy Mechanisms of skeletal pattern formation in

the vertebrate limb; Neodifferentiation of brown adipocytes

Noto, Richard, MD Pediatrics (Pediatric Endocrinology) Pediatric Endocrinology

Ojaimi, Caroline, PhD Pathology The use of gene array technology and functional genomic approaches in vascular biology

Olson, Susan C., PhD Biochemistry and Molecular Biology Vascular Endothelium

Parton, Lance A., MD Pediatrics (Neonatology) NeonatologyParvez, Borianna, MD Pediatrics (Neonatology) NeonatologyPetzke, Mary, PhD Microbiology and Immunology Host-pathogen interface between the

mammalian immune system and Borrelia burgdorferi

Pinto, John Thomas, PhD Biochemistry and Molecular Biology Prevention of primary and secondary prostate cancer development through diet-derived factors

Powers, C. Andrew, PhD Pharmacology Integrative physiological mechanisms contributing to the effects of estrogens and antiestrogens on energy balance; Bone and lipid metabolism; Growth and cardiovascular function

Prashad, Priya S., MD Pediatrics (Pediatric Pulmonology, Allergy and Sleep Medicine)


Reilly, Michael, Dr.PH Emergency Medicine Disaster medicine; Pediatric Emergency Preparedness; Preparedness for Persons with Disabilities; Blast Injury; Analysis of Emergency Preparedness in other countries

Sabban, Esther L., PhD Biochemistry and Molecular Biology Molecular basis of the neurochemical responses to stress

Scharbach, Marilyn, MD Pediatrics (Pediatric Pulmonology, Allergy and Sleep Medicine)


Schwartz, Ira, PhD Microbiology and Immunology Emerging tick-born infectious diseasesSchwartzman, Michael L., PhD Pharmacology Development of hypertension in metabolite

Sehgal, Pravin B., MD, PhD Cell Biology and Anatomy Membrane-associated trafficking of STAT3; Pulmonary arterial hypertension

Seligman, Karen, MD Pediatrics (Pediatric Cardiology) Pediatric CardiologyShapiro, Lawrence R., MD Pediatrics (Medical & Biochemical

Genetics)Medical Genetics

Sharma, Sansar, PhD Cell Biology and Anatomy Retinal-ganglion cell death with experimentally induced glaucoma

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Faculty Department Research InterestSiegel, Subhadra, MD Pediatrics (Pediatric Pulmonology,


Sorrentino, Susanna, MD Pediatrics (Medical & Biochemical Genetics)

Medical Genetics

Springer, Alan D., PhD Cell Biology and Anatomy Causes of retinal detachments in premature infants; Causes of strabismus

Stanton, Patric K., PhD Cell Biology and Anatomy Cellular mechanisms of synaptic plasticity that underlie learning and memory, and how these mechanisms contribute to neuropathologies such as epilepsy and stroke-induced delayed neuronal death

Stewart, Julian M., MD, PhD Pediatrics (Pediatric Cardiology) Pediatric CardiologyStier Jr., Charles T., PhD Pharmacology High blood pressureTiwari, Raj K., PhD Microbiology and Immunology Designing and testing of cancer vaccinesTraeger, Nadav, MD Pediatrics (Pediatric Pulmonology,


Traganos, Frank, PhD Pathology Interaction between the various activating and inactivating events of cell proliferation

Velisek, Libor, MD, PhD Cell Biology and Anatomy Investigation of the animal model of infantile spasms

Veliskova, Jana, MD, PhD Cell Biology and Anatomy Mechanisms by which sex hormones influence neuronal excitability during physiological conditions scuh as synaptic plasticity and during pathological processes (Seizures & seizure-induced damage)

Wandel, Thaddeus, MD Opthalmology Glaucoma Schunts and Glaucoma Blood Tests

Wang, Wen-Hui, MD Pharmacology Neural diseaseWarsy, Irfan, MD Pediatrics (Pediatric Cardiology) Pediatric CardiologyWelter, John, MD Pediatrics (Pediatric Pulmonology,


Williams, Gary M., MD Pathology Chemical CarcinogenesisWu, Joseph M., PhD Biochemistry and Molecular Biology Quinone Reductase 2 as a novel target of

chemoprevention and cardioprotection by resveratrol

Zaidman, Gerald, MD Opthalmology Corneal DiseasesZeman, Richard, PhD Cell Biology and Anatomy Rehabilitation following spinal cord injuryZhang, Zhongtao, PhD Biochemistry and Molecular Biology Neurological disorders related to Aging

Zia, Muhammed, MD Pediatrics (Neonatology) Neonatology

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research opportunities 2015-2016 · together with dr. john pinto i am interested in the metabolism...

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