Despite improvements in air quality over the past few decades, research shows that elevated levels of particulate matter air pollution (called PM10) are associated with an increase in cardiovascular disease (CVD) and death. More than 800,000 deaths a year can be attributed to PM10-induced CVD, including life threatening irregular heartbeats, atherosclerosis, heart attack and stroke. Diesel exhaust particulates are the major contributor to PM10 in most urban centres worldwide. But there is little evidence to describe how these particulates affect cardiovascular function. The endothelium is a monolayer of cells separating blood from the vascular wall, thus providing physical and biological protection. Importantly, endothelium plays a major role in protecting, activating and controlling cardiovascular function. Activation of endothelium is implicated in the development of atherosclerosis. Ni (Nicola) Bai is investigating whether exposure to diesel exhaust particulates induces dysfunction in these cells, causing the progression of atherosclerosis, and ultimately leading to heart attack and stroke. The findings should help develop interventions that minimize or prevent deaths associated with breathing polluted air.
Research Pillar: Biomedical
Investigation of the role Cnk2p plays in ciliary length control
Eukaryotic cilia are membrane-bound organelles in cells known for their function to propel cells (such as sperm cells), or move fluid over a cellular surface (such as respiratory epithelial cells in the lungs). More recently, researchers have looked more closely at immotile (unmoving) primary cilia which are found on almost all terminally differentiated mammalian cells (mature cells that no longer grow). Previously believed to have no function, immotile primary cilia have now been shown to have significant signalling roles and are gaining recognition as sensory organelles. A series of recent discoveries has pointed to the idea that the cilia found in tubular epithelial cells of the kidneys are required for maintaining the differentiation of kidney tubules, and that the loss of this function results in Polycystic Kidney Disease, a common human genetic disease also found in other species. Focusing on one member of a family of proteins known as the NIMA-related kinases, Brian Bradley is studying the connections between cilia, the processes by which they are assembled, and cell division. He hopes his work can lead to a better understanding of the role of cilia in human health and disease.
Tissue Specific Functions of ABCA1
An individual’s cholesterol levels – both LDL (or “bad” cholesterol) and HDL (or “good” cholesterol) – are known to be a significant predictor of the risk for heart disease. While much attention has been focused on lowering levels of LDL, much less is known about the factors that determine HDL levels and how to alter these levels. However, research suggests that every 1 per cent increase in HDL levels results in an approximately 2-3 per cent decrease in risk for cardiovascular disease. With insight into how to raise HDL levels, a majority of the population might avoid developing heart disease. The gene ABCA1 has been identified as crucial to the production of HDL cholesterol, and is expressed in many tissues in the body. However, it is unclear which specific cell types or organs are responsible for the generation of HDL particles. Liam Brunham is investigating the specific role of ABCA1 in different tissues of the body and determining how ABCA1 in these tissues responds to different genetic and dietary environments. This research will increase the understanding of how ABCA1 functions to determine HDL levels, and suggest new ways to protect against heart disease.
Characterization of the role of the Fas-associated death domain (FADD) protein in lipopolysaccharide signalling in endothelial cells
Sepsis is a life-threatening medical condition caused by a severe bacterial infection. It is a leading cause of death in critically ill patients, with mortality rates reaching greater than 60 per cent in its most critical forms. Endothelial cells, the layer of cells that line the inside wall of blood vessels, are a primary target for bacteria during infection. Major components present on the surface of some types of bacteria are recognized by molecules on the surface of the endothelial cell and can trigger the cells to release a class of chemicals that initiate an inflammatory response, characterized by redness, heat, swelling and pain. Under normal conditions, the body will protect itself by initiating this response. However, sepsis occurs when there is hyperactivation of the inflammatory response and the body fails to resolve the infection. This can result in endothelial cell damage, leading to major organ failure and death. Lipopolysaccharide (LPS) is a large molecule that forms an integral part of the outer wall of some bacteria. Exposure to this molecule signals cells to activate the inflammatory response and, in the case of endothelial cells, leads to cell death. Shauna Dauphinee is investigating whether a protein called FADD (Fas associated death domain) decreases the signalling ability of LPS, thereby reducing the inflammatory response and causing cell death. The results of this research could ultimately lead to new ways to treat sepsis.
Biological pathways disrupted in mantle cell lymphoma pathogenesis
Mantle cell lymphoma (MCL) is an aggressive, incurable non-Hodgkin lymphoma with a median survival of three years. In order to find new, more effective treatments for MCL, researchers are working to better understand how the disease develops and progresses. MCL is characterized by a specific gene translocation, which prompts an unregulated growth signal. However, this translocation is believed to be only the first event in a stream of genetic alterations required to cause the disease. Using a recently-developed test capable of pinpointing previously undetectable genetic alterations, Ronald deLeeuw is compiling a more complete catalog of the secondary genomic alterations associated with MCL. By uncovering the role of secondary genes within the progression of MCL, Ronald hopes to uncover new targets for disrupting these pathways and halting the disease.
Dissecting the Modular Structure of the Secreted Glycoside Hydrolase Exotoxins of Clostridium perfringens: Catalysis and Carbohydrate Recognition
Clostridium perfringens is found ubiquitously throughout the environment, present in soil, and the gastrointestinal tract of animals. When people eat improperly cooled food contaminated with C. perfringens, toxins are produced in the intestinal tract causing the symptoms of food poisoning. In developing countries necrotic enteritis, or pig-bel may develop, a life-threatening disease that attacks the intestines. The bacterium also causes the severe medical condition gas gangrene where, once infected, the progression of the disease is very rapid and often results in fatality. Elizabeth Ficko-Blean is studying the mechanism by which two toxic enzymes, secreted by C. perfringens, are involved in the ability of the organism to cause disease. Elizabeth wants to determine whether the toxins enable the bacterium to spread infection in a wound and degrade human tissues. The findings may contribute to the development of new drugs to inhibit these enzymes, decreasing their toxic effect, and allowing antibiotics more time to fight the progression of the bacteria.
Computational analysis and modeling of the Myelin Basic Protein gene regulation
Faulty gene regulation is implicated in a wide variety of diseases. Gene regulation is the process cells use to translate genetic information into proteins (gene expression) which control (regulate) all aspects of cell growth and function. The myelin sheath is a soft, white insulating layer that forms around nerve cells and enables rapid, efficient transmission of nerve impulses. Myelin basic proteins (MBP) are required for normal myelin compaction in the central nervous system, and alterations in MBP gene expression may be implicated in debilitating human myelin disorders such as multiple sclerosis. Debra Fulton is collaborating with scientists at McGill University in Montreal to develop a computation model of MBP gene expression. This will include the development of a database to house and support detailed interrogation of experimental inputs, outputs, and interactional relationships. Illumination of the gene regulation program governing MBP gene expression is fundamental to the discovery of regenerative therapies that encourage the stabilization of myelin, or initiate myelin repair after injury. A detailed investigation focused on learning how transcription of this gene is activated or repressed is one means to unravelling the regulatory program.
Role of galectin-1 in regeneration and repair following nerve injury
Neurons (nerve cells) send information from skin and muscles along projections (axons) for integration in the brain or spinal cord. Injury to neurons and their axons can result in loss of sensory and motor function. Injury to the axons within the central nervous system (CNS), which includes the brain and spinal cord, can be especially devastating since they cannot regrow. In the peripheral nervous system (PNS), axons do have some capacity to regrow, but often fail to reconnect with proper targets in muscle and skin, leading to permanent loss of motor function and chronic pain. Andrew Gaudet is investigating the role of a protein called galectin-1 (Gal1) in regeneration after nerve injury. Increasing the levels of Gal1 in the area around the injured axon promotes axonal regrowth, and neurons that contain high levels of Gal1 can regrow better than those that do not have Gal1. Andrew is using mouse models to study the effects of different levels of Gal1 on the ability of axons to regrow in the central and peripheral nervous systems. By providing new insight into the mechanisms underlying regeneration, this research may lead to better functional recovery following peripheral nerve or spinal cord injury.
Trafficking of neuroligins during the formation of excitatory and inhibitory synapses
The brain is made up of millions of neurons that transmit signals to one another across synapses. An imbalance in the number of excitatory (glutamatergic) and inhibitory (GABAergic) synapses in the brain is believed to underlie complex neurological disorders such as autism and schizophrenia. Kimberly Gerrow was previously funded by MSFHR to investigate the molecular stages of synapse development in the hippocampus. Now, she is working to bring further understanding to the basic principles that dictate the number and strength of excitatory and inhibitory synapses in the brain. Specifically, she is investigating the role of a pre-assembled postsynaptic complex of scaffold proteins, which she hypothesizes dictates the number and strength of contacts formed between young neurons during development. She hopes her work may lead to new potential targets for therapy.
Combatting antibiotic resistance in MRSA: the structural biology of beta-lactam resistance regulation by the protease domain of Staphylococcus aureus protein BlaR1
Antibiotic resistant infections are becoming more widespread, posing serious threats to human health. For example, Staphylococcus aureus bacteria are common on the skin of healthy people, but can cause serious infections if they penetrate the skin and enter the body. The antibiotic, methicillin, effectively treats most “staph” infections, but some bacteria have developed a resistance. As a result, MRSA (methicillin-resistant staphylococcus aureus) outbreaks can be life-threatening in hospital wards, especially for patients with compromised immune systems. Even more worrisome is that new strains of MRSA that can infect and harm otherwise healthy people – called ‘community MRSA’ – are on the rise across Canada. Michael Gretes is investigating how MRSA bacteria turn their resistance genes off and on using two proteins. The first protein keeps the resistance turned off. Another protein has a scissor-like part. With no antibiotics around, the scissors are closed. When penicillin or methicillin is administered to try to kill the bacteria, the scissors receive a signal to cut the first protein, turning the antibiotic resistant genes on. Michael is x-raying protein crystals to determine how the scissor functions. This information may lead to new drugs to keep the scissors locked, which could be combined with antibiotics for patients with antibiotic resistant infections.