Building on his earlier research, which was supported by a MSFHR Trainee Award, Damon Poburko is now investigating the mechanisms involved in mitochondrial regulation of calcium. An average cell has several hundred mitochondria, which provide the energy for cells to function properly. Research has shown mitochondria are involved in programmed cell death, or apoptosis, when they take up large, toxic loads of calcium. In addition, mitochondria sense calcium changes, allowing them to tailor energy production to cell needs. Mitochondria also help regulate intracellular calcium levels, which determine blood vessel constriction in vascular muscle. The findings should help explain how vascular tone is regulated, and how blood is shunted to different parts of the body as needed. Ultimately, this research may lead to the development of new therapies to treat vascular diseases.
Research Location: Children's & Women's Health Centre of British Columbia
Pain in preterm infants
Dr. Ruth Grunau is a world expert on the measurement and long-term consequences of pain in newborns and premature infants in neonatal intensive care units. From the late 1980s, when she conducted landmark research on measures for assessing pain in infants, she has continuously added to the body of research concerning how early pain experiences in very low birthweight infants may affect their clinical and developmental outcomes. Dr. Grunau is conducting several studies on pain and stress in fragile premature infants whose medical care involves repeated exposure to invasive procedures. She is studying how to distinguish pain from stress in very premature infants, and how pain, sedation and analgesia may affect their neurobehavioural development. She is investigating the effects of repetitive pain on attention, behavioural organization and development in very premature infants and toddlers. Finally, she is studying whether positive maternal interaction may moderate the potentially negative effects of neonatal intensive care unit experiences. By learning the most effective ways to minimize any detrimental consequences caused by early repetitive pain and stress, Dr. Grunau’s goal is to help clinicians improve the short- and long-term outcomes of very premature infants.
Pharmacogenetics of codeine metabolism to morphine in pediatric dental patients
Pharmacogenetics-the study of how genetic makeup affects an individual’s response to drugs-fascinates Evan Kwong. The field addresses the underlying causes of why drugs may affect people differently, bringing the study of genetics into a practical, clinical setting. In the future, having access to a patient’s genetic profile could help clinicians more quickly and accurately select the right therapy. Evan’s research focuses on the common painkiller codeine, which produces pain relief as it is metabolized into morphine by a liver enzyme. A genetic variation in 25 to 40 per cent of people of Chinese descent appears to be associated with decreased function of this liver enzyme. Evan hopes to determine whether people who carry this genetic variation metabolize codeine less effectively. With that knowledge, clinicians could offer other drugs that will be effective.
The roles of valvular myofibroblasts and endothelium in the development of human cardiac valvular disease
Vascular disease is the largest single cause of death in developed nations, and the incidence of cardiac valvular disease (disease in heart valves) is significant. The first cells to be adversely affected in vascular disease are endothelial cells, located on the inner lining of blood vessels. In the initial stages of vascular disease, there are modifications to the way endothelial cells regulate calcium signaling, an essential part of communication between cells. Willmann Liang is studying normal and abnormal calcium regulation in two types of heart valve cells: endothelial cells and myofibroblasts (cells involved in wound healing). Willmann aims to understand how calcium regulation in the human cardiac valve is altered with disease, and to determine how gene expressions governing the various components of calcium signaling are modified. Ultimately, the research may lead to the early prevention and treatment of valvular diseases.
Function and mechanism of genomic imprinting on mouse chromosome 6
Along with the completion of the Human Genome Project have come new insights and tools to understand complex gene interactions. Dr. Louis Lefebvre’s work focuses on genomic imprinting, an inheritance process that works counter to the traditional genetic rules. Genes are inherited in two copies – one from the father and one from the mother. Usually, the outcome in the offspring will depend on whether genes are dominant or recessive. With certain genes, however, the inheritance is parent-of-origin-specific: the gene will always be inherited by either the mother or father, with the corresponding gene from the other parent maintained in a silent state. This type of inheritance is thought to be especially important for the development of the embryo and in adult tissues. Defects in imprinting are associated with a variety of disease syndromes. Dr. Lefebvre is studying the mechanisms of genomic imprinting. He hopes to identify new genes required for normal development and better understand the origins and causes of human syndromes that are associated with abnormal imprinting.
Endocrine mechanisms of bone mass and structural changes in prepubertal, over-and normal weight Asian and Caucasian boys: Associations with increased exercise and body composition
Based on her previous research on pediatric bone health, Dr. Kerry MacKelvie believes that perhaps the greatest hope for preventing osteoporosis in later life is to intervene during childhood. Kerry has studied how high impact exercise affects bone mass and structural changes during growth, and she has investigated the effects of ethnic background on bone health. Now Kerry is bringing together in one study an investigation of all the factors that may contribute to bone strength during childhood: exercise, hormones, body mass and composition, and ethnicity. She will study Asian and Caucasian boys who have not yet reached puberty, focusing on bone mass changes over time for both overweight boys and inactive boys. The study is particularly relevant to Vancouver’s population, as it will examine and compare ethnic-specific hormonal, body composition and bone mass changes during growth in both Asian and Caucasian children.
Identification of components necessary for proper chromatid cohesion by global expression profiling
The error-free duplication of a multicelled organism’s genetic material is critical to its survival. Even small changes in the genetic code during duplication can lead to diseases such as cancer. Equally important to cell division is the error-free transmission of chromosomes to each of the two daughter cells, which depends on the proper regulation of sister chromatid cohesion (the attachment of both strands of newly-replicated DNA to the area of the chromosome called the centromere). When the mechanisms involved in chromatid cohesion are defective, there may be uneven segregation of chromosomes to daughter cells. This results in abnormal chromosome numbers (aneuploidy), a characteristic of many cancers. Ben Montpetit is studying the components responsible for regulating cohesion of sister chromatids. Ben’s research is aimed at providing a better understanding of what happens when the cohesion process is flawed, and to help identify therapeutic targets in cells with defects due to altered chromatid cohesion.
The role of huntingtin interacting proteins (HIPs) in the pathogenesis of Huntington's disease
Huntington disease (HD) is a neurodegenerative disorder that causes uncontrollable movements, impairment in memory and reasoning ability, and alterations in personality. Patients with the disease carry a mutation in the HD gene, which results in an expanded tract of glutamine (an amino acid). The gene product is therefore a mutated form of the HD protein. This expanded tract disrupts the interaction between the HD protein and other proteins that work together to perform essential cell functions. A modified interaction may alter the normal function of any of the interacting proteins, making specific cells vulnerable to premature death. Anat Yanai is studying the cell biology of several HD interacting proteins, including the way they interact with proteins involved in cellular metabolism and the alterations in their normal function as a result of the mutation in the HD gene. The findings will assist in developing therapeutic strategies for Huntington patients, such as inhibitors or activators of these interactions.
Dietary lipids in growth, development and health
My research focuses on the role of dietary fat in providing essential fatty acids to support growth and development, including long-term effects on children’s physical, cognitive and behavioural health. I am investigating how specific fatty acids influence brain development and nerve function, the dietary intakes needed to ensure optimal development, and the role of altered fatty acids in disorders such as liver disease and cystic fibrosis. Clinical applications of this research have ranged from developing special feeds to support optimal brain development in premature infants, to research into diets for prevention of seizures and liver damage in children with cystic fibrosis. I also head a nationally funded Nutritional Research Program exploring how our genetic makeup blends with our nutritional intake, particularly in the maternal and early childhood period, to affect our life-long susceptibility to disease. Findings will provide important new information about tailoring nutritional intake to meet individual needs in health and disease.
Hepatitis A virus infections among children in British Columbia: Is routine vaccination needed?
Hepatitis A is a viral disease that causes inflammation of the liver. Once contracted, there is no treatment. Adults and older children with the disease usually suffer for four to ten weeks, and the symptoms include jaundice, fatigue, abdominal pain and fever. Young children usually have mild, symptom-free cases that go unrecognized, but can transmit the virus to people of all ages. The BC infection rates for hepatitis A virus have exceeded the national average for more than a decade. Yet a safe, effective vaccine has been available since 1994. The vaccine is currently only given to high-risk groups, and most cases reported by physicians come from these groups. I am investigating the risk of hepatitis A for children in two areas of BC that consistently report high infection rates. The study will determine whether universal childhood immunization is warranted. We can gauge risk for hepatitis A by testing saliva for antibodies to the virus, which would indicate a past infection. Our research team has tested about 800 randomly selected grade nine students. Students also filled out a questionnaire on potential risk factors. We are analyzing this data to identify why the hepatitis A rates may be higher in these areas and whether the scope of the disease is broader than reported cases indicate. If we find high rates of past infection, routine vaccination may be warranted. If low rates are found, the results will provide reassurance that existing sanitary measures are adequate to protect local children.