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.

Central pathways mediating testosterone effects on hypothalamic responses to stress

The hypothalamic-pituitary-adrenal (HPA) axis is a brain-hormone system that plays an important role in the body’s reaction to stress. The HPA axis controls the secretion of glucocorticoids – steroid hormones that are released from the adrenal glands during stressful episodes. In the short term, acute elevations in circulating glucocorticoids are beneficial, serving to meet the metabolic demands of stress by mobilizing energy stores. In the long term, however, chronic stress-induced elevations in glucocorticoids are implicated in several forms of systemic, neurodegenerative and affective disorders, including depression. Dr. Viau is working to determine the sites and mechanisms by which testosterone acts in the brain to regulate the HPA axis. Given the association of chronic stress with depression and the potency by which testosterone inhibits stress-HPA function, Dr. Viau is investigating where stress, testosterone, and depression intersect in the brain. Dr. Viau hopes his discoveries will be taken from the bench to the bedside, towards implementing sex steroid replacement as an adjunct to antidepressant therapy.

Secondary prevention – the gap between evidence and practice

Cardiac disease remains the leading cause of death in Canada. A significant portion of cardiac health care resources are expended on acute interventions such as clot-busting drugs, angioplasty and bypass surgery. However, there is a lack of research on the use of proven strategies – known as secondary prevention – to prevent patients from experiencing subsequent coronary events such as a heart attack. Dr. Karin Humphries is a leading investigator in the area of cardiac health outcomes and the epidemiology of cardiovascular disease. Dr. Humphries is studying how BC patients with heart disease are monitored and how many are using aspirin, beta-blockers and cholesterol-lowering drugs as part of their efforts to reduce their risk of further coronary events. Eventually, she hopes to design a clinical trial to assess new approaches to increase the use of secondary prevention strategies.

Airway epithelial injury as a result of corticosteroid-induced apoptosis

In people living with asthma, the cells lining the airway are more sensitive to injury from allergens and other irritants. Researchers have found that these cells have an impaired ability to repair themselves following injury. Dr. Delbert Dorscheid is studying how the inhaled corticosteroids that asthmatics use to control their symptoms may actually contribute to ongoing breathing problems. While corticosteroid benefit asthmatics by suppressing the inflammation of the airway, Dr. Dorscheid’s research has shown that corticosteroid use also causes the death of cells lining the airway. In severe asthmatics, this may create a cycle of repeated injury and incomplete repair that results in permanent damage. Dr. Dorscheid’s is assessing the extent to which corticosteroids may cause permanent damage to airways and also clarifying the mechanisms by which these drugs cause cell death. His goal: the development of treatment options that will have fewer damaging side effects.

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.

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.

Structural analysis of the bacterial Sec-dependent protein secretion system

Cells have compartments separated by membranes. Many proteins are made in one compartment but actually function in another. The ability of proteins to travel across membranes within cells is essential to cell life. Malfunctions in this process can lead to a variety of inherited and autoimmune diseases in humans. Dr. Mark Paetzel’s research focuses on the mechanisms by which proteins travel across cell membranes, a process called protein targeting and translocation. Using the technique of X-ray crystallography, Dr. Paetzel is uncovering the three-dimensional structures of the protein complexes that make up the molecular machines involved in bacterial protein targeting and translocation. A better understanding of the functions and mechanisms of these protein complexes may yield insights about how the process works in human cells. In addition, learning how the process differs between bacteria and human cells could lead to a novel class of antibiotics that can shut down protein targeting and translocation activities in bacteria, but leaves human cells unaffected.

The demand for hereditary cancer services

The Hereditary Cancer Program at the BC Cancer Agency provides genetic testing and counseling services. The demand for these services in BC depends on many factors, each of which is subject to change. Factors include the growing knowledge in basic, applied and social sciences relating to hereditary cancer; the size of BC’s population and its characteristics in terms of age, ethnicity and family size; the evolving criteria by which people are deemed eligible for services; and people’s desire for these services. Through his research, Dr. Chris Bajdik is determining the demand for hereditary cancer services in BC and predicting how this demand may change in the future. He has created a computerized simulation model of the BC population, based on information about demography, cancer epidemiology and etiology, genetics, genetic technology, and human behaviour. The results from this model will help the BC Cancer Agency plan its services and assess the health benefits and costs of its Hereditary Cancer Program.

Cell therapies for the treatment of hematopoietic malignancies

Though small in numbers, stem cells are responsible for the continued production of blood cells throughout a person’s life. They are also responsible for regenerating the blood-forming system following a bone marrow transplant in people with leukemia and other blood diseases. While blood stem cell transplantation is a promising therapy, its use is currently restricted because researchers have not yet found a way to reproduce these cells in large enough numbers for effective transplantation. Dr. Clayton Smith’s research is devoted to developing a better understanding of blood-forming stem cells so they can be effectively isolated and manipulated. Using leading-edge bioengineering and computer-based technologies, he is systematically exploring how the body’s environment affects stem cell growth, to see if these conditions can be replicated outside the body. He is also studying the function of certain genes that may be important to stem cell growth. Ultimately, he hopes to learn enough about stem cells to be able to grow them in large numbers outside the body for use in blood stem cell transplantation.

Adverse drug effects among persons using antiretroviral therapy for HIV Disease and impact on treatment patterns

Antiretroviral drugs successfully suppress the HIV virus and reduce mortality, but many people living with HIV and AIDS cannot benefit fully from the medication due to adverse side effects. These side effects make it difficult for people to take the drugs consistently, or at all. Many side effects do not become apparent until after people have taken antiretroviral drugs for a prolonged period. Dr. Katherine Heath is establishing a monitoring system to track adverse reactions to antiretroviral drugs, identify and describe newly emerging side effects, and assess the impact of these side effects on antiretroviral use in BC. Dr. Heath-based at the BC Centre for Excellence in HIV/AIDS, which houses the only North-American population-based database of information on people using antiretroviral drugs-hopes her research will enable early detection of trends or new side effects, lead to early intervention and ultimately improve the health of people living with HIV and AIDS.