Gene Therapy for a genetic cardiovascular disease: AAV-mediated gene transfer of a powerful, naturally occurring, LPL-S447X variant for the treatment of LPL deficiency

Dr. Colin Ross believes that studying genetics and diseases at the molecular level can open many doors for the treatment of diseases at their root causes. He’s doing exactly that in cutting edge research to develop treatments for a genetic cardiovascular disease that has the highest worldwide frequency in Canada’s French-Canadian population. People with lipoprotein lipase (LPL) deficiency are missing a key enzyme that helps break down triglycerides (fats) in the blood stream. Elevated levels of these fats can cause serious, life-threatening damage to the pancreas, heart and other organs. Ross is working on the development of gene therapy techniques to implant healthy genes into cells to restore production of the missing enzyme. He ultimately aims to develop a safe and long-term treatment for LPL deficiency.

Gonadotropin-releasing hormone (GnRH) in reproductive biology and medicine

The long-term goal of my research is to understand the multi-faceted role of gonadotropin-releasing hormone (GnRH), the primary regulator of the reproductive process. Our brains release GnRH to the pituitary gland, where it stimulates the synthesis and release of the gonadotropin hormones that regulate gonads (ovaries and testes). My research has shown that GnRH also affects cell function in the ovaries and placenta and the hormone may play a role in controlling estrogen and progesterone production. GnRH has a role in both normal ovarian physiology and in the development of ovarian cancer. Ovarian cancer is a major cause of death, but little is known about the way it develops. We are seeking new knowledge that will help us understand the role of GnRH in the development of ovarian cancer, which should lead to more effective treatments in future. We also know GnRH affects the successful implanting of an embryo to establish a pregnancy and the formation of placenta, but that process is not well understood. My research will help explain the causes and process of fertility. Synthetic GnRH compounds are often used in different areas of reproductive medicine, such as fertility and sterility, ovulation control and assisted reproduction. This research will provide a better understanding of the cellular and molecular effects of these compounds and should improve clinical applications as a result.

Family influence in pediatric chronic pain and disability

Up to 15 per cent of school-aged children and adolescents suffer from chronic pain conditions such as recurrent headaches and abdominal pain. Children with chronic pain frequently miss considerable amounts of school, do not participate in athletic and social activities, and suffer depression or anxiety. The family plays an important role in influencing how children learn to deal with pain, but little is known about how this learning occurs. My research will identify how families influence children’s responses to pain. I will compare studies of children between the ages of eight and 15 with chronic pain and disability with pain-free children and their parents. The research will examine how families interpret pain symptoms, how parents make decisions about their children’s complaints of pain, parents’ thoughts about their children’s pain, and parent-child behaviour during pain episodes. In addition, I am studying how health care providers and parents assess pain in children and the tools that we use with children to measure pain. My research will also explore the relationship between sleep disturbances and chronic pain in children, an area of research that has been overlooked until now. The results of these research studies will help family members and health care providers better manage children’s pain, and will help improve treatment and prevention of disabling pain in children.

Characterization of the Ctf3/Mcm22/Mcm16 outer kinetochore complex; a link to the yeast spindle pole body

In order for cells to grow properly, chromosomes must accurately separate to opposite poles of the dividing cell. Mistakes in this process can lead to cancer due to instability of the chromosomes. Dr. Vivien Measday is using a yeast model to study chromosome segregation. She has a particular interest in the centromere, the region of the chromosome required for proper segregation, and the kinetochore, which consists of centromere DNA and its associated proteins. Using genetic screens, Measday is identifying and characterizing kinetochore proteins. Studying these proteins will increase understanding of why chromosomal instability occurs in cancer cells and in other disorders such as Down’s syndrome.

Analysis of altered gene expression in YAC transgenic mouse models for Huntington disease

Research has confirmed that an inherited mutation in the huntingtin protein causes Huntington disease, a progressive and ultimately fatal neurological disorder that usually starts in mid-life. There is much more to be learned about the onset and course of the disease and there is no effective treatment. Dr. Edmond Chan is addressing those gaps by profiling gene expression in mice with Huntington disease. His research aims to identify altered patterns of gene expression that link with early, mid and late stages of the disease. The profile may identify genes involved in initiating the process that leads to progressive damage and death of brain cells. Chan will formulate and test specific theories that connect gene expression patterns with the molecular development of Huntington disease. Ultimately, genes identified in the research could suggest treatment strategies to improve quality of life for patients with the disorder.

Utilization of large-scale genomic yeast modifier screens in the identification of unique genes required for chromosome segregation

Chromosome segregation is a fundamentally important process for human cells. When cells divide, they normally ensure both daughter cells receive one copy of each chromosome. But defects in this process can cause cells to lose chromosomes or receive extra ones. Inaccurate chromosome segregation can lead to diseases such as cancer. Despite the importance of this process, researchers are just beginning to identify and understand the genes and molecular mechanisms involved. Dr. Kristin Baetz is investigating the genes and mechanisms needed to ensure accurate chromosome segregation. Baetz is developing a genomic screen to identify unique genes in a genetic yeast model, whose genome and cell biology are remarkably similar to that of humans. Building knowledge about chromosome instability could lead to new treatments for common forms of cancer.

Lymphocyte defects in X-linked lymphoproliferative disease

Dr. Ala Aoukaty has spent nine years investigating anti-viral and anti-tumour cells. Aoukaty’s doctoral research focused on understanding the signalling process that occurs after receptors on the surface of cells are engaged. That experience provided him with a strong background to conduct postdoctoral research on X-linked lymphoproliferative disease (XLP), a fatal disorder caused by a genetic mutation and characterized by severe infectious mononucleosis, immune deficiency and malignant lymphomas (tumours). A large Aboriginal family that carries the genetic mutation has been identified. Aoukaty will isolate and study cells from XLP patients and carriers of the disease in the family to study the abnormal immune responses at work. The research will shed light on how the immune system specifically responds to Epstein-Barr virus, which causes infectious mononucleosis, provide insights in general about lymphoproliferative disorders (diseases of immune system tissue), and enable the testing of gene replacement therapies.

Pathogenesis and Treatment of Huntington's Disease

There is currently no effective treatment for Huntington’s disease, a progressive and ultimately fatal neurological disorder caused by a defect in the Huntington Disease gene. Symptoms of the inherited disease, which usually appear at mid-life, include abnormalities in movement, difficulties with awareness and judgement, and emotional instability. Using genetically altered mice, Jeremy Van Raamsdonk is investigating the underlying genetic and cellular changes that give rise to Huntington’s disease and potential treatment strategies. The research involves testing both drug and gene-based treatments targeted at the root cause of the disease, as well as assessing treatments to minimize the damage to the nervous system. By developing specific treatment strategies, Van Raamsdonk aims to limit damage to nervous system cells and increase the lifespan and quality of life for people with Huntington’s disease.

Prediction and prevention of autoimmune diabetes mellitus

Jacqueline Trudeau’s research focuses on autoimmune disease – disorders that cause the immune system to destroy normal body tissues. She’s specifically interested in how a specific type of immune cell, T-cells, are mistakenly activated in autoimmune disorders. Type 1 diabetes is an autoimmune disease in which T-cells destroy insulin-producing B-cells in the pancreas. This leads to hyperglycemia (high blood glucose), insulin dependence and other complications associated with diabetes. Given that autoimmune diseases may develop and be present for years before being diagnosed, they are difficult to treat. It is also challenging to understand how the disease process is initiated and the course of development thereafter. Jacqueline is developing techniques to identify T-cells that specifically destroy B-Cells before hyperglycemia sets in. She aims to design an approach for identifying children at the early stage of developing diabetes, a critical window of opportunity when treatment could save remaining B-cells

Temperature Dependence of the Cardiac Sodium Calcium Exchanger

Mortality associated with open-heart surgery is two to three times higher in newborns than in adults. Christian Marshall believes this is due to a lack of knowledge about heart function in newborns, including how the neonatal heart responds to surgery. He’s focusing, in particular, on the inability of newborn heart cells to control calcium levels. When unregulated, calcium can initiate destructive events leading to cell death. Marshall is examining the effects of changes in temperature on the sodium-calcium exchanger (NCX), a protein in the heart cell membrane that is key to calcium regulation. Since surgeons need to reduce the temperature of the heart to perform open-heart surgery, and much of the cell damage occurs when warming the heart after surgery, Marshall is seeking a better understanding about temperature effects on NCX. He hopes this will reveal ways to reduce cell death during heart surgery and contribute to a better survival rate for these tiny patients.