Genes – the functional units of DNA – are involved in all aspects of normal human development and human disease. Although most cells have a core set of active genes, selective activation of other genes is necessary to produce different types of specialized cells, such as muscle cells, nerve cells and skin cells. Malfunction in the normal pattern of gene activation is implicated in many diseases, including cancer. Dr. Jones uses sophisticated computational techniques to analyze the activation of genes involved in the formation and development of mammalian organs and tissues and to explore genes that are activated in specific cell types such as muscle and neural cells. His goal is to develop software that will allow researchers to predict the behaviour of genes by indicating when they are switched “on” or “off”. Besides improved understanding of normal growth and development, this research will help clarify the changes in activation patterns that give rise to cancer, potentially leading to new ways of detecting cancer risk and the earliest stages of cancer onset.
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Genetic modifiers of pulmonary disease severity in cystic fibrosis
Cystic fibrosis is a severe genetic disorder caused by a single gene called the cystic fibrosis transmembrane regulator (CFTR). The disease is characterized by chronic and persistent respiratory infections, which progressively damage and eventually destroy lung function. Research has shown that cystic fibrosis patients with the same alteration in the CFTR gene may each follow a very different clinical course: with one patient having very mild lung disease and infrequent lung infections, while another will have frequent lung infections and significantly decreased lung function. Dr. Andrew Sandford is investigating genes other the CFTR gene that may play a role in causing lung disease to progress more quickly in some cystic fibrosis patients than in others. It is thought that cystic fibrosis patients may also have compromised immune function. For this reason, Dr. Sandford is looking for genes involved in fighting infections and in controlling the inflammatory response to the bacteria and viruses that attack the lungs.
Chronic psychological stress and immune system dysregulation
Research has shown that chronic stress negatively affects health. One model suggests that chronic stress suppresses immune function, leaving people more vulnerable to infectious diseases and cancers. However, it doesn’t explain how stress affects conditions that result from over-activation of the immune system, such as autoimmune, arthritic and cardiovascular disorders. To investigate how stressors interfere with the immune system’s ability to turn itself off once activated, Dr. Miller is comparing the immune responses of two groups: parents with a severe chronic stressor (a child undergoing cancer treatment), and parents of healthy children. Results from the research could increase knowledge about the ways stressors affect health, including confirmation that one of the effects is interference with the immune system’s ability to turn off responses against bacteria. As part of this study, Dr. Miller is also examining whether supportive personal relationships act as a buffer against chronic stress.
CHIPS (control of hypertension in pregnancy study): a pilot trial
Almost 10 per cent of women who become pregnant develop hypertension (high blood pressure). Experts agree that pregnant women with severe hypertension should receive blood pressure medication to protect them from stroke. However, it is not clear if or how much the medication would benefit pregnant women with mild to moderate hypertension. A complicating factor is that the medication may also contribute to poorer growth and lower birth weight in babies, placing them at increased risk for health problems as newborns, children and adults. According to a national survey, Canadian obstetricians are unsure about prescribing blood pressure medication to women with mild to moderate hypertension. To help clarify the issue, Dr. Laura Magee and her research team have designed a Control of Hypertension in Pregnancy Study (CHIPS), aimed at determining if it is better for the baby (i.e. better growth before birth and better health thereafter) to allow a mother’s blood pressure to be higher than normal during pregnancy or to prescribe blood pressure medication to lower it. To begin, Dr. Magee is conducting a pilot trial to assess whether or not physicians would adhere to the treatment protocols in a full trial and to confirm if sufficient patients could be enrolled. If the pilot study indicates that CHIPS is feasible, the full trial will be conducted at major maternity centres across Canada.
Regulation and role of granzyme B in Atheromatous Diseases
Atherosclerosis – hardening of arteries – is caused by buildup of plaque inside artery walls. This constricts blood flow and elevates blood pressure, and is the leading cause of heart attacks, stroke and lower limb loss due to poor circulation. There is evidence that immune cells provoke a tightly-regulated form of cell death known as apoptosis (programmed cell death) in atherosclerotic blood vessel walls, which contributes to progression of the disease. While the mechanisms are not clearly understood, the result is a change in the architecture of blood vessel walls that leads to additional plaque build-up and also to plaque instability. The latter increases the danger of pieces of plaque breaking off and potentially lodging in and blocking blood flow in smaller vessels. In previous work, Dr. David Granville and his research team have found that an enzyme used by the immune system to kill abnormal and infected cells is released in atherosclerotic blood vessels. Dr. Granville is studying the role of this enzyme – granzyme B – in vessel wall restructuring and cell death associated with atherosclerosis and transplant vascular disease. Findings from this research may reveal new opportunities for intervening to prevent or treat these vascular disorders.
Drug-related mitochondrial toxicity in HIV and HCV antiretroviral therapy: impact of mitochondrial DNA/nuclear DNA ratio changes on therapy outcome
Triple combination antiretroviral therapy has greatly reduced the rate at which people with HIV infections progress to AIDS. However, the medications used in the therapy can be quite toxic, leading to serious liver, kidney, muscle and nerve problems and reducing the length of time patients are able to tolerate the treatment. Dr. Hélène Côté and colleagues at the BC Centre for Excellence in HIV/AIDS have developed a blood test to measure toxicity from antiretroviral therapy and are now assessing its effectiveness in detecting and monitoring toxicity levels. She is also investigating whether the test could predict complications from drug therapy before serious symptoms appear. If so, it could be used to tailor use of antiretroviral therapy and improve treatment outcomes. As part of the research, Dr. Côté also is studying the effectiveness of the blood test in measuring toxicity of medications used for hepatitis C.
Translating mechanistic understanding of the systemic inflammatory response syndrome (SIRS) to clinical practice via genomics
Each year, about 75,000 patients in Canada will develop sepsis (severe infection). Although it is reversible, sepsis often causes death. Sepsis and a related condition, systemic inflammatory response syndrome (SIRS), lead to multiple organ dysfunction and are the most common reasons for admission to intensive care units. Using genetic information that became available after completion of the human genome project, Dr. Keith Walley is researching the genetic determinants of the acute inflammatory response and organ failure associated with sepsis. His aim is to clarify the genetic mechanisms which give rise to the inflammatory response and to apply this information to identify patients who are at risk for adverse outcomes based on their genotype (genetic make-up). His ultimate goal is individualized management of patients with sepsis, based on knowledge of the way their genotype will influence their susceptibility to and risk of developing life-threatening symptoms, as well as their ability to respond to treatment.
Leptin regulation of glucose homeostasis
More than two million Canadians have diabetes, a chronic metabolic disorder caused by the inability of the body to produce or properly use insulin. Obesity is a risk factor for developing type 2 diabetes, the most common form of the disease. Dr. Timothy Kieffer has uncovered links between leptin – a hormone that affects how the body manages and stores fat – and insulin producing beta cells of the pancreas, plus the liver, one of insulin’s target tissues. His research suggests there may be a defect in the interaction between leptin, fat, beta cells and liver cells. Using genetic engineering approaches, Dr. Kieffer is investigating the role of leptin in the development of diabetes and obesity, in the hopes of eventually developing novel therapeutic strategies to combat these debilitating diseases.
Mammalian organelle-membrane Type Na+/H+ exchangers
The cell is the basic unit of structure and function in the body. Many of the functions of cells are performed by particular subcellular structures called “organelles”. Acidity (pH balance) is important for organelle function and disruptions in this environment can lead to uncoordinated communication between brain cells, compromised immunity and uncontrolled cell growth or death. Dr. Masayuki Numata is studying the mechanisms for pH regulation in cells. Dr. Masayuki Numata and his research team have isolated ion transporter proteins that may regulate acidity inside organelles. Using biochemical, cell biological, genetic and immunological techniques, he is investigating how these transporters are delivered to the right destination when they are needed and how they are regulated by different factors. The research could ultimately increase understanding of the mechanisms by which brain cells transmit signals to each other and how disruptions in these signaling pathways cause damage leading to Alzheimer’s disease and other neurodegenerative disorders.
Regulation of NMDA receptors and excitotoxicity
Glutamate mediates signaling between neurons (nerve cells) by binding to protein receptors. Over-activation of one type of glutamate receptor, NMDA, can result in damage to neurons. Dr. Lynn Raymond is researching how neuronal activity and cell proteins regulate NMDA receptors, with the goal of better understanding how irregularities or disruptions in regulatory pathways are implicated in damage associated with neurological disease. Dr. Raymond is especially interested in Huntington’s Disease. This inherited neurological disorder causes progressive neurological damage in specific brain regions leading to movement abnormalities, personality changes, psychiatric disorders and memory loss. Studies have suggested that over-activation of NMDA receptors plays a major role in this selective destruction of brain cells. Dr. Raymond is investigating interactions between mutant huntingtin (the protein produced by the Huntington’s Disease gene) and NMDA receptors to gain a more detailed understanding of the causes of neuronal death in Huntington’s Disease – research that may help in the development of new therapies for this incurable disease.