Tuberculosis is a devastating disease that infects one-third of the worldâs population, leading to eight million new cases and three million deaths per year. The prevalence of this disease is largely due to the ability of Mycobacterium tuberculosis (the bacteria that causes tuberculosis) to evade destruction by the immune system. Normally, when bacteria invade the body, the human response system triggers specialized cells called macrophages to engulf and destroy bacteria. In the case of tuberculosis, M. tuberculosis succeeds not only in escaping annihilation, but is able to enter and live inside the very cells that are programmed to destroy it. Using yeast as a model organism, Emily Thi is studying and identifying the components of the arsenal that Mycobacterium tuberculosis uses to successfully infect and survive within human macrophages. Her research on M. tuberculosis proteins that disrupt normal macrophage function may lead to the identification of novel targets for drug and vaccine development, which could result in new strategies to combat this challenging disease.
Program: Trainee
The Role of CREB in Long-term Memory in Caenorhabditis elegans
Currently 30 million Americans suffer from some form of clinically recognized memory disorder. During the last 25 years, basic neurobiological research has begun to identify the underlying molecular mechanisms for memory formation. One of the key players discovered to be involved in the formation of protein synthesis dependent long-term memory (LTM) is the transcription factor cAMP response element binding protein (CREB). CREB has been shown to be a necessary protein for the formation of LTM in diverse species including sea hares, fruit flies, mice and humans. Tiffany Timbers is exploring whether CREB is also essential for the long-term habituation observed in Caenorhabditis elegans (a tiny nematode), which can become âused toâ repeated stimulation such as tapping on the Petri dish where it lives. Tiffany will determine whether CREB activity (resulting in the transcription of cAMP responsive genes) occurs in the neurons that generate the plasticity responsible for LTM. By investigating the involvement of CREB in the biological pathway underlying the memory of habituation in C. elegans, this research could contribute to the development of new gene targets, drug screens and preclinical data to suggest drug classes capable of helping those affected by memory cognition defects.
The Cell Biology of the NIMA-Related Kinase Defective in Polycystic Kidney Disease
Polycystic kidney disease (PKD) affects one in 800 people worldwide and is the major reason for dialysis treatment and kidney transplantation. One of the most common genetic diseases in the world, PKD has many forms, ranging from aberrant cell proliferation in the kidney to defects in other organ systems, such as the liver and pancreas. This abnormal growth within kidneys and other organs eventually leads to organ failure. The age of onset and disease severity for PKD are highly variable and are affected by additional genetic mutations. Mouse models of the disease have been used to identify many of the genes involved in the polycystic pathology and to determine links between gene and disease. Many of these genes encode proteins that localize to the cilia, a hair-like cell projection that senses the extracellular environment of the cell. The loss of a cilium results in the inability of a cell to response to external cues controlling normal growth. It has been shown that the failure of a kidney cell to build cilia results in PKD. Nek8 is an enzyme which, when mutated, causes PKD in mice. Melissa Trappâs work has shown that Nek8 is also found within the cilia. This research project is focused on the role of Nek8 within cells, particularly how mutated Nek8 can alter the cilium and cause defects in cell growth. By manipulating the protein levels in Nek8 within cultured kidney cells and introducing mutant forms of Nek8, she is examining the effects on ciliary assembly and cell proliferation. This research will contribute to the body of knowledge accumulating about Nek8 and the cause of PKD. It could also contribute to our understanding of other cystic kidney diseases.
Determination of the Effect of Cardiac Ischemia on Ion Channel Kinetics Using Real Time Voltage Fluorimetry
Potassium channels play an essential role in controlling the activation of neurons (nerve cells), myocytes (muscle cells) and the endocrine system. In particular, their proper function and behaviour in the heart is of the utmost importance in maintaining proper cardiac function. Acidosis (a lowering of blood pH) is caused by cardiac ischemia, or an insufficient blood supply. It has been shown that acidic pH levels alter ion channels, possibly through a structural change in the pore region. This condition is linked to cardiac abnormalities such as arrhythmias and cardiac arrest. Moninder Vaid is focusing on acidic alteration of cardiac ion channel function to determine how pH modulates ion channel structure. He using fluorescent techniques to further examine how ion channels work in mammals. Ultimately, this research will provide insight into the effects of cardiac ischemia.
Exploring RNAi technology for the treatment of Huntington's disease
Huntingtonâs 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 diseaseâs greatest underlying pathological insult, the muHtt protein itself. Laura Wagnerâs 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.
Neurexins and Neuroligins in Synapse Development
Messages are relayed through the nervous system by release of neurotransmitters from an axon of one neuron, which travel across the synaptic cleft and bind to receptors on a dendrite of the next neuron. The axon terminal, synaptic cleft and dendrite are collectively called the synapse. The formation of synapsesâknown as synaptogenesisâis the most central process in the development and maintenance of the nervous system. New synapses are formed during learning and memory and the maintenance of synapses can be altered in disease and drug-induced states. Katherine Walzakâs research is focusing on the process by which synapses form and change with experience. Specifically, she is exploring how neurotransmitter receptors on postsynaptic dendrites are aligned with neurotransmitter release sites on presynaptic axons, and how cell adhesion molecules influence synapse differentiation and localization. By understanding the mechanisms by which synapses forms and are maintained, this research may lead to further insights into disease that may involve the alteration of synaptogenesis, such as Alzheimerâs, schizophrenia and autism spectrum disorders.
Dynamic Risk Factors for Violence in People With Major Mental Disorders
Major mental disorders are associated with increased rates of violence, which is a primary reason for involuntary psychiatric or community treatment for individuals with mental disorders. Within psychiatric inpatient units, violence compromises the safety of hospital staff and other patients, adversely impacts staff morale, jeopardizes the therapeutic setting, and presents a risk of physical injury. In order to prevent violence, it is important to identify the factors that can provoke violent outbursts. Certain known risk factors for violence do not change during a personâs life, such as their age at a first violent incident or early childhood maladjustment. However, there are also dynamic risk factors â such as emotional distress, treatment compliance, and symptoms of psychosis â that can and do vary over time. Catherine Wilson is studying a group of psychiatric inpatients admitted for treatment of a major mental disorder. Using specialized methods, she will measure these dynamic risk factors over time, from admission to discharge. The findings of Catherineâs study will increase our theoretical understanding of violence and assist the development of treatment and management programs designed to prevent violence by psychiatric inpatients.
The development and evaluation of a novel hybrid exercise rehabilitation program for the improvement of the health-related quality of life and overall health status of persons with spinal cord injury
More than 35,000 Canadians are living with spinal cord injury (SCI), and recent research indicates that this population is at an increased risk for chronic disease, particularly cardiovascular disease. In fact, individuals with complete tetraplegia (paralysis of all four limbs) are at a markedly greater risk of death resulting from cardiovascular disease in comparison to the able-bodied population, due to factors such as obesity, inactivity, increased risk for blood clots and lower levels of âgoodâ cholesterol (HDL). Hybrid exercise training (involving the concurrent exercise of the arms and legs) is thought to have the potential to lead to marked improvements in the overall health status of persons with SCI. However, no investigations have been performed to evaluate and define the best hybrid exercise program for the treatment and rehabilitation of persons with SCI. Shirley Wongâs research is focused on developing and evaluating a novel intervention program involving hybrid exercise training for persons with SCI. The ultimate goal of Shirleyâs research is to reduce the risk for chronic disease and improve the overall health status and quality of life for persons living with SCI.
First Nations Women Leaders: Building a Bridge from Cultural Identity to Healthy Youth
In British Columbia, First Nations youth are five to 20 times more likely to die by suicide than their non-Aboriginal peers. These youth suicide rates, however, are not uniformly high across the almost 200 First Nations communities in BC. Research has found that suicide rates are lowest in those communities that have been especially successful in preserving and promoting their cultural heritage and in securing local control over key aspects of community life. More recently, it has been found that suicide rates are lower in communities where women actively participate in their local government. Robin Yates is exploring the relationship between First Nations women leaders, cultural identity, and lower suicide and injury rates of youth in BC First Nations communities. The results of her research will enhance the development and exchange of knowledge regarding factors that preserve and promote healthy youth in First Nations communities.
Ex vivo Engineering of Gut K-cells to Produce Insulin
Diabetes is a leading cause of death in Canada, affecting more than two million Canadians. Type 1 diabetes occurs when the pancreas fails to produce insulin, a hormone that is vital to transforming the sugars ingested in a meal to useable forms of energy. As a result, diabetic patients often depend on multiple daily injections of insulin to survive, but these injections do not prevent a series of long-term complications such as increased risk of heart disease, kidney disease and blindness. Type 1 diabetics can be treated by transplantation of isletsâcell clusters from the pancreas containing insulin-producing cellsâfrom non-diabetic donors. However, this option is severely limited by a shortage of donor islets. Therefore, there is interest in generating other cells that can also produce insulin. To be effective and safe, such cells must be capable of producing insulin in an amount that matches the quantity of sugar ingested. Like the insulin-producing islet cells, there are cells in the gut that are activated after a meal. These cells do not produce insulin, but another protein called glucose-dependent insulinotropic polypeptide (GIP). Recently, scientists were able to genetically modify these gut cells to produce insulin in addition to GIP. Building on this discovery, Irene Yu is working to develop methods to isolate and purify these cells and to determine how long these genetically modified cells can survive after transplantation. She is also testing whether these cells can effectively maintain normal blood glucose levels. If so, there will be an alternative to islets that can be used for transplantation, providing more type 1 diabetes patients with a longer-lasting treatment option.