Heart disease, diabetes and other complex diseases involve genes that combine with lifestyle and environmental factors to increase disease susceptibility. To find the genetic factors that influence disease outcomes, researchers have begun using haplotypes – sets of closely linked genetic variants inherited together as a unit. However, the use of haplotypes introduces its own complexities, including uncertainty in haplotype measurement, handling of rare haplotypes and the optimal length of haplotypes to examine. By incorporating the genetic relatedness of haplotypes into statistical estimation, Kelly Burkett hopes to address these points to more effectively predict the effects of haplotypes on disease outcomes. The methods will not only enable researchers to identify genetic risk factors but also the connections between genetic and non-genetic factors, such as lifestyle, environmental and occupational risks. The identification of such risk factors is hoped to eventually lead to improved disease treatment and prevention by highlighting new drug targets and lifestyle modifications for those with increased disease susceptibility.
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Obsessive-Compulsive Checkers' Prospective Memory
Obsessive compulsive disorder (OCD) is characterized by persistent, unwanted thoughts (obsessions) and/or repetitive behaviors (compulsions). One of the most common manifestations of OCD is checking compulsions, where an individual is obsessed with the idea that they failed to do something, or failed to do it correctly (e.g., locked the door or turned off the stove). The OCD sufferer will feel compelled to repeatedly check that the task was completed in order to be satisfied that it was in fact completed, and/or completed properly. These obsessions and compulsive behaviours can be so pervasive and time-consuming that people with OCD have difficulty functioning at work, performing routine activities and relating to others. Many types of compulsive checking behaviours appear to be linked to prospective memory, defined as the ability to formulate intentions, plans and promises, to retain them, to recollect and carry them out appropriately. Carrie Cuttler’s preliminary research suggests that checking compulsions may develop to compensate for an impaired prospective memory—caused by either a real deficit, or by an individual’s own perception and beliefs about their “bad memory”. Now, she is conducting studies to compare prospective memory between non-checkers and checkers. By exploring the relationship between prospective memory and compulsions, Carrie hopes her research will point to ways to help OCD patients minimize their behaviours and anxieties, and improve their quality of life.
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.
Identification of regulatory mutations involved in cancer by gene expression analysis and bioinformatics approaches
Regulatory DNA sequences determine the leveI, location and timing of gene expression. These sequences are important in nearly all biological processes and many disease conditions. In some cases, the onset of cancer is related to changes in these sequences, such as when gene translocation results in the production of a protein that prevents normal cell death. Expanding on his previous MSFHR-funded work, Obi Griffith will make use of public gene expression data and novel computational approaches to identify genes believed to have undergone a change in regulation leading to cancer. Once these genes have been identified, further analysis will investigate the mechanism responsible for the change in regulatory control. Then, Obi will obtain specific tumour samples and validate the predicted changes in the laboratory. Obi hopes to increase understanding of how genes are controlled under normal conditions and how the loss of this control leads to cancer. Such identified genes could make suitable targets for therapeutic intervention as well as having prognostic and diagnostic value.