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.

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.

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.

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.

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 caspase modifiers via genetic selection in yeast

Elaine Law’s Masters research literally related to matters of life and death. Elaine investigated apoptosis – the process of programmed cell death. Apoptosis plays a critical role in normal body function by eliminating unwanted and potentially dangerous cells as part of tissue renewal. However, too much cell death can lead to strokes and neurodegenerative disorders such as Alzheimer’s Disease and Huntington’s disease, while too little cell death has been associated with many forms of cancer and autoimmune diseases. Using yeast as a host and advanced genetic techniques, Elaine studied caspases, a group of proteins that play a key role in cell death. She developed a genetic selection system in yeast for identifying caspase modifiers: proteins that either activate or inhibit caspases. Her research improves understanding of cell death and provides insights about genes that contribute to abnormal patterns of cell death leading to cancer.

Calcium Homeostasis and Basal Entry in Vascular Smooth Muscle

Much research has been devoted to understanding how calcium enters stimulated vascular smooth muscle and causes muscle contraction. Defects in this process have been linked to diseases such as hypertension and peripheral vascular disease. But little research has been done on calcium entry in unstimulated muscle. Damon’s research suggests that a significant amount of calcium enters muscle even in the absence of a contraction-inducing stimulus. By investigating the pathways through which calcium enters vascular smooth muscle and skeletal muscle, Mr. Poburko aims to identify the specific role of calcium entry in causing diseases such as muscular dystrophy and chronic hypertension. Ultimately the research may point to new drug therapy targets for the diseases.

The involvement of phosphatidylcholine in the development of hepatic steatosis in children with cystic fibrosis

Alice Chen hopes to achieve a better understanding of what causes liver disease in people with cystic fibrosis (CF). Liver disease – the second most common cause of death for people with CF – may result from depletion of choline (a water soluble B vitamin) in CF patients. An inability to properly absorb phosphatidylcholine (PC), which is found in food such as organ meats and egg yolks, may cause choline depletion and may ultimately lead to accumulation of fat in the liver. To test this hypothesis, Chen is studying a group of 50 children with CF, along with 10 healthy children. She will collect and analyse data from these children to determine if there is a link between difficulty in absorbing PC and liver disease. Chen, whose goal is pursing a career in nutrition research, believes that a better understanding of the causes of liver disease in people with CF is critical for the development of nutrition interventions that could prevent this serious complication.

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.