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Molecular and Cellular Biology:Exploring the Architecture of Life

Marc Coppolino

Department of Molecular and Cellular BiologyUniversity of Guelph

Molecular and Cellular Biology

Tariq AkhtarEmma Allen-VercoeMark BakerAndrew BendallManfred BrauerMalcolm Campbell Anthony Clarke Joseph ColasantiMarc CoppolinoGeorgina CoxJohn DawsonMichael EmesSteffen GraetherGeorge Harauz

Nina JonesDavid JosephyAzad Kaushik Cezar KhursigaraMatthew Kimber Jasmin LalondeRay Lu Jaideep Mathur Baozhong MengRod MerrillRichard MosserRobert Mullen Lucy Mutharia

Annette NassuthMelissa PerreaultSteven RothsteinScott RyanStephen SeahRebecca ShapiroIan TetlowJim UniackeGeorge Van der MerweTerry Van RaayJohn VesseyChris WhitfieldKrassimir Yankulov

BiochemistryMicrobiology

Molecular BiologyAnd Genetics

Molecular and Cellular Biology

Botany

Neuroscience

Molecular and Cellular Biology

Tariq AkhtarEmma Allen-VercoeMark BakerAndrew BendallManfred BrauerMalcolm Campbell Anthony Clarke Joseph ColasantiMarc CoppolinoGeorgina CoxJohn DawsonMichael EmesSteffen GraetherGeorge Harauz

Nina JonesDavid JosephyAzad Kaushik Cezar KhursigaraMatthew Kimber Jasmin LalondeRay Lu Jaideep Mathur Baozhong MengRod MerrillRichard MosserRobert Mullen Lucy Mutharia

Annette NassuthMelissa PerreaultSteven RothsteinScott RyanStephen SeahRebecca ShapiroIan TetlowJim UniackeGeorge Van der MerweTerry Van RaayJohn VesseyChris WhitfieldKrassimir Yankulov

bacterial surfacesProtein structure and function

Host-pathogeninteractions

Cancer biology

Human gut microbiome

Stress response in yeast

Virology

Developmental/Cell biology

Plant metabolism

Eukaryotic signaltransduction

Molecular and Cellular Biology

Neuroscience of agingand disease

In MCB, researchers strive to understand how cells work. By examining the molecules that make up cells, we will ultimately understand the inner workings

of the basic unit of life - the cell.

Our primary motivation: DISCOVERY

The molecular basis of cells is common to all life

The Prokaryotic Cell (e.g bacteria)

The Eukaryotic Cell(e.g. human liver cell)

Cells… many shapes many sizes many interactions

This gives rise to emergent (and most amazing!) properties of life…

Multicellularity

Interactions between cells, and betweencells and their environment, are thefoundation of multicellular life

What determines and maintains the architecture of cells, tissues and organs?

Examples of Research in MCB

Cezar Khursigara- Bacterial cell division target for novel antibiotics

Tariq Akhtar- Analysis of secondary metabolites in plants

Terry Van Raay- Developmental mechansims in Zebrafish

Matt Kimber- Bacterial proteins involved in CO2 fixation

Rebecca Shapiro- Genomic approaches to study fungal pathogens

George Van der Merwe- Regulation of fermentation in wine yeast

Dr. Nina JonesCellular Interactions that Regulate Kidney Function

glomerulus

podocytes

A protein called ‘nephrin’ allows connections between podocytes in the kidney - forming a filter

In many kidney diseases, disruption of nephrin function impairs filtration

The Role of Brain Waves in Communication within the Central Nervous System

Dr. Melissa Perreault

Alterations to brain waves are associated with several disorders, for example: Alzheimer’s disease Schizophrenia Depression

What are brain waves?

Rhythmic, repetitive electrical impulses in a group of neurons cause ‘waves’.

Brain waves result from rhythmic or repetitive neural activity

CRUCIAL TO BRAIN COMMUNICATION Changes in brain wave patterns at specific

frequencies contribute to a number of central nervous system diseases

Brain wave

What are brain waves?

In humans, brain waves can be taken through the scalp EEG

Animal models are an essential tool to further our understanding of brain functions

• Unlike humans, brain waves from many regions can be assessed observe broader, brain-wide activity

• Drug-effects ex. antidepressants, antipsychotics• Timelines are possible for early-to-late stage disease• Correlations of brain wave patterns with behaviour

Mood disorders Addiction Obesity

Diseases such as Alzheimer’s, schizophrenia, and depression are associated with altered brain wave patterns that contribute to cognitive dysfunction

Depression: lifetime prevalence of ~15% in Canada; twice as common in women

Current antidepressant therapies are limited

Characterized by asymmetries in brain waves between left and right frontal cortex

Involves function of specific molecules(e.g. proteins serotonin receptor)

What can we learn about cognitive function from studying brain waves?

1. Are there innate sex differences in brain wave patterns?2. Can brain wave patterns predict depression susceptibility? 3. Can these patterns be used to identify novel therapies?

Dr. Scott RyanInvestigating the cellular basis of neurological disorders

e.g. Parkinson’s disease

Parkinson’s Disease

Parkinson’s disease is characterized by accumulation of aggregated proteins in brain cells

Leads to cognitive decline Brain has limited capacity to

generate new cells

Production of cells in tissues is carried out by stem cellsStem Cells – can divide indefinitely, make multiple cell types, and exists for the life of the organismCan Parkinson’s disease be treated with stem cells?

Adult brains have limited capacity to produce more brain cells!

How can we get more stem cells?

Molecular and cellular technologies can be used to generate stem cells

* Specifically for individual patients

biochemistry of bacterial toxins involved in disease

Dr. Rod MerrillBiochemical analysis of bacterial toxins and their role in disease

Many bacteria produce toxins that are deadly to cells These toxins are released by bacteria, so even if the

bacteria are eventually eliminated, the toxin can persist Presents many challenges to fighting infection

e.g. cholera, whooping cough, agricultural diseases

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Apis mellifera (European honey bee)

• Originally domesticated for honey

• Contribute to global food stores

• Declining populationsParasitesDiseases

American Foulbrood

• Causative agent: Paenibacillus larvae

• Targets the brood of the colony

(Modified from Müller et al., 2015)

American Foulbrood

(Simon et al., 2014)

P. larvae produces a protein toxin (C3larvin) very similar to that of Vibrio cholerae

ADP-ribosyltransferase (enzyme) These toxins enzymatically alter proteins in

infected cells kills cells

Using chrystallography, structural proteomics, and biochemistry, Dr. Merrill’s group is working to identify ways to block the toxin

Cell Migration and invasionin tumour progression

Marc Coppolino

Department of Molecular and Cellular BiologyUniversity of Guelph

Abnormal cell movement drives the spread of cancer

Malignant tumour cells invade neighboring tissue

In tissues, cells exist, and move, within a 3-dimensional environment

- surrounded by external protein matrix

Cell

ExtracellularMatrix (ECM)

Tumour cell invasion requires enzymes that breakdown the protein matrix outside cells.

Tumour cells secrete theseenzymes

invadopodium

t-SNAREs

MT1-MMPMMP

integrin

Degradation of the matrix is a highly organized process- structures calledinvadopodia

These structures can be studied biochemically and microscopically

Src EGFRTks5 overlay

Src F-actinEGFR overlay

Invadopodia as seen under the microscope

F-actin overlayY845-EGFR zoom

What cellular components are required for cancer cells to invade other tissues?

How do invadopodiaform?

invadopodium

t-SNAREs

MT1-MMPMMP

integrin

MT1-MMPF-actin

Control

overlay

shRNASNAP23

GFP

shRNASyntaxin4

SNARE proteins are required for the formation of invadopodia

Ultimately, we hope to stop tumour cells from doing this, in order to prevent this

Molecular and Cellular Biology

Discovering the cellular and molecular architecture of life….

Thank you!