Fraz Ahmed Ismat, MDClinical Associate in Pediatrics, Division of Cardiology

The Children’s Hospital of Philadelphia

The Ras-t of the story…

Intracellular signaling incardiovascular development & disease

Nf1-/- embryos die of cardiovascular failure

Jacks T. et al., Nat Gen 1994

Nf1-/- hearts have a lethal series of defects

wild typee13.5

Nf1 -/-

e13.5

Gitler, et al., Nat Gen 2003

GRD expression rescues Nf1-/- embryonic heart defects

NF1 GRD expression rescues pericardial effusion ( ), enlarged endocardial cushion (arrows), and myocardial thinning (arrowheads).

*

Ismat et al., JCI 2006

GRD expression rescues Nf1-/- embryonic lethality

Nf1+/+ 13 17 27

Nf1+/+, GRDk/+ 13 17 13

Nf1+/+, CMV-cre+ 13 17 15

Nf1+/+, GRDk/+, CMV-cre+ 13 17 17

Nf1+/- 26 35 22

Nf1+/-, GRDk/+ 26 35 40

Nf1+/-, CMV-cre+ 26 35 37

Nf1+/-, GRDk/+, CMV-cre+ 26 35 32

Nf1-/- 13 0 0

Nf1-/-, GRDk/+ 13 0 0

Nf1-/-, CMV-cre+ 13 0 0

Nf1-/-, GRDk/+, CMV-cre+ 13 0 5*

Genotype Mendelian Expected Observed

Genotypes of 208 P0 pups from Nf1 +/-, GRD k/+ × Nf1 +/-, CMV-cre +.

Ismat et al., JCI 2006

Generation of Nf1 myocardial “knock-out” (Nf1mKO)

Late mortality in Nf1mKO

n=23

n=20

Progressive cardiac hypertrophy & fibrosis in Nf1mKO

Cardiac dilation & reduced shortening in Nf1mKO

Rescue of Nf1mKO cardiac hypertrophy with NF1 GRD

Marin, et al., JCI (in press)

LEOPARD syndrome mice have enlarged hearts

Wild type LS/+

Rapamycin rescues LS/+ cardiac hypertrophy

LS/+ LS/+ rapamycin

0.0054

0.0056

0.0058

0.006

0.0062

0.0064

0.0066

0.0068

0.007

0.0072

0.0074

WT LS LS + Rapa

**

HW

/BW

Rat

io

Marin, et al., JCI (in press)

Wild type

Acknowledgements

Past support: a Young Investigator Award from the Children’s Tumor Foundation, a Physician Scientist Development Award (K08) from the NHLBI;

Current support: a Basil O’Connor scholarship from the March of Dimes Foundation, a cardiovascular research grant from the W.W. Smith Charitable Trust,

and grants from the CHOP Cardiac Center Scientific Review Committee.

Ismat LabAlmedia McCoyTimothy Macatee

MCRC Core FacilitiesHistology Core (MM Lu)Transgenic Core (D Zhu)Physiology Core (T Wang*)

Penn Core FacilitiesFlow Cytometry & Cell SortingSmall Animal ImagingMicroarray Core Facility

Collaborators & Others

Jonathan Epstein (Penn)Aaron Gitler (Penn)Elizabeth Goldmuntz (CHOP)Tyler Jacks (MIT)Maria Kontaridis (BIDH-HMS)Thomas Look (DFCI)Arun Padmanabhan (Penn)Luis Parada (UTSW)Nancy Ratner (Cincinnati)Xin Zhang (IUPUI)Yuan Zhu (Michigan)