Research Location: Child & Family Research Institute

Type 2 diabetes mellitus is a devastating chronic disease affecting close to two million Canadians. The disease is characterized by a loss of insulin action in tissues such as muscle and a loss of insulin secretion by the islet beta cells of the pancreas. The number of beta cells within the pancreas – an important determinant of the amount of insulin secreted – is decreased in persons with type 2 diabetes. This supports the idea that the progressive loss of insulin secretion in this disease is due to a loss of functional beta cells. The loss of beta cells is associated with the formation of toxic islet amyloid deposits, consisting primarily of the beta cell peptide islet amyloid polypeptide (IAPP or amylin). Although the mechanism underlying islet amyloid formation is not known, impaired processing of the IAPP precursor, proIAPP, has been proposed to be an important initiating event. In type 2 diabetes, elevated glucose and free fatty acids can cause beta cell dysfunction, which raises the question whether elevated cholesterol induces beta cell dysfunction in this disease. Zainisha Vasanji’s research is aimed at determining whether exposure of beta cells to elevated cholesterol is the trigger for the chain of events that lead to islet amyloid formation in type 2 diabetes. Zainisha’s study may help delineate the cause of the beta cell defect in type 2 diabetes and may lead to new therapies to prevent the progressive loss of insulin secretion in this disease.

Huntington’s disease (HD) is a progressive neurological disorder characterized by involuntary movements, emotional disturbances and memory loss. There is currently no cure for HD, and the disease is ultimately fatal. HD is caused by a selective loss of a population of nerve cells in specific regions of the brain, particularly the striatum. Accumulating evidence suggests that overactivation of glutamate receptors (transmembrane proteins involved in communication between nerve cells), which are abundant in the striatum, might lead to the selective death of nerve cells observed in HD. Mahmoud Pouladi’s research focuses on evaluating the efficacy of small molecule therapeutics known to target glutamate receptor signalling pathways in a model of HD. His work explores whether restoring physiologic levels of intracellular calcium by modulating glutamate signalling will prevent the neurodegeneration and associated motor and behavioural deficits observed in HD. This study will further our understanding of this disease and provide insights about glutamate signalling as a therapeutic target for the treatment of HD.

Bacterial infections in the intestine cause diarrheal disease worldwide, affecting people of all ages. These bacteria also trigger inflammatory conditions of the digestive tract such as in Crohn’s disease and ulcerative colitis which can lead to chronic illness and hospitalization. Growing evidence suggests that the innate immune system is critical in regulating the body’s response to early infection, and recent research suggests that dysfunction of this innate response may contribute to Crohn’s disease. A strain of Escherichia coli (E. coli) that attaches to cells on the inner lining of the intestine is a major cause of diarrhea in children, but little is known about the mechanisms by which the immune system recognizes and responds to this type of bacterial infection. Mohammed Khan is investigating how the innate immune system detects E. coli infection and the mechanisms that regulate subsequent inflammatory events in the intestine. Using laboratory-grown human intestinal cells and mouse models, Mohammed hopes to reveal novel mechanisms of regulation of inflammation in host defense. This research may lead to new treatments for infectious and inflammatory diseases of the human intestine.

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.

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.

Vesicle transport is a process that underlies various molecular events, such as the movement of glucose transporters in response to insulin in muscle and fat cells. Malfunctions in these transport processes can result in a range of problems, including diabetes or problems in learning and memory formation. An important but unclear aspect of vesicle transport is how molecules are retained within specialized compartments in the cell and how they are released to the cell surface. Chris Tam’s research goal is to identify proteins that control the storage and release of molecules in yeast cells. She is doing this by conducting high-throughput genome-wide screening to uncover yeast genes that are required for the intracellular storage of the protein Chs3. As the basic cellular mechanisms that regulate vesicle transport are likely conserved in both yeast and humans, this understanding from yeast cells may provide insights into various fundamental aspects of human biology. Ultimately, this work may contribute to the development of new treatments for diabetes and diseases involving memory and learning deficits.

Huntington’s disease (HD) is a debilitating genetic disease affecting approximately one in 10,000 individuals. HD is the most common inherited brain disease and is caused by an abnormal protein called mutant huntingtin (muHtt). Symptoms of the disease include cognitive impairment, motor dysfunction and psychiatric disturbances that usually develop around midlife. Many treatments are under investigation in mouse models of HD to potentially cure this debilitating disease. While some pharmacological agents show promise in treating HD, most act on isolated or late-onset symptoms that fail to target the disease’s greatest underlying pathological insult, the muHtt protein itself. Laura Wagner’s research is exploring RNA interference (RNAi), a natural cellular mechanism with intriguing therapeutic potential to block production of the muHtt protein in hopes of slowing or preventing HD symptoms before they start. She is using a transgenic model of HD to test RNAi constructs and their ability to prevent muHtt expression in the brain. The model will be monitored for brain changes as well as behavioural and motor function improvements as indicators of the effectiveness of RNAi treatment. In addition to testing a novel treatment for HD, this research will contribute to continued efforts in advancing medical care from a late-stage symptomatic approach to earlier, preventative therapies such as gene-targeted treatments.

Calcium that is released from one part of a smooth muscle cell can sometimes travel along the length of the same cell in a wave-like manner. This phenomenon is known as a calcium wave. Under certain conditions, a calcium wave can synchronize with other calcium waves from neighbouring cells to cause rhythmic contractions of blood vessels, known as vasomotion. Why vasomotion occurs is not completely understood, but it may be important in controlling blood flow in small diameter blood vessels, such as the cerebral arteries in the brain. Cerebral arteries regulate the flow of blood to working areas of the brain, but this flow is compromised during conditions such as stroke, hypertension or diabetes. There is evidence that the frequency of vasomotion is affected in these conditions. Harley Syyong is studying vasomotion and its underlying mechanisms. Using both molecular and ultrastructural methods, he is exploring the contribution of calcium waves to vasomotion. This research will explore how calcium waves are generated, their role in vasomotion and how the physical structure of the cell supports their propagation. This project is laying the groundwork for future studies to examine how the underlying mechanisms of vasomotion are affected during pathological conditions such as stroke, hypertension and diabetes. Ultimately, this may lead to new drug therapies for treatment of these conditions.

In Type 1 diabetes, beta cells are destroyed by the immune system, leaving the body unable to produce insulin. Type 1 diabetic patients inject insulin several times a day to normalize their blood glucose levels. Estimating the correct dose of insulin to administer is difficult: too much insulin leads to hypoglycemic shock, while chronic hyperglycemia (a shortage of insulin) can lead to organ damage and related complications such as blindness, kidney failure, neuropathies, vascular damage and pain in the limbs. The transplantation into diabetics of insulin-producing islet cells shows promise for relief from daily insulin injections and the development of diabetic complications. However, islet transplantation is in the early stages, and long-term rates of transplanted islet graft survival and maintained function are low: only 10 per cent of islet transplanted recipients remained free from insulin injections five years post-transplantation. Kathryn Potter is working to better understand the mechanisms underlying graft failure. In particular, she is interested in how stressors unrelated to immunity—such as pre-transplant and post-transplant hyperglycemia and the use of immunosuppressants—may cause dysfunction in transplanted beta cells and lead to graft failure. Her research may lead to modifications to current transplantation protocols that improve long-term islet transplantation success rates.