Truncation of huntingtin and its relationship to the pathogenesis of Huntington's Disease

Huntington disease (HD) is a fatal degenerative brain disorder caused by a defective gene, which causes cells in specific parts of the brain to die. This leads to symptoms including progressive deterioration in the ability to control movements and emotions, recall recent events or make decisions, and leads to death 15 to 20 years after onset. One in 10,000 Canadians has HD, and children with a parent with HD have a 50 per cent risk of inheriting the disease. There is neither a cure nor treatments to prevent Huntington disease. The HD gene produces a protein called huntingtin, which breaks into short fragments that dramatically promote cell death. Little is known about the exact function and toxic properties of this mutant protein. Now Rona Graham is expanding her earlier Masters research into the mechanisms that cause shortened huntingtin. She is investigating other forms of mutant huntingtin to determine their role in creating HD, and hopes the results will lead to new therapies to prevent or alleviate this disease and other neurodegenerative disorders.

Role of alveolar macrophage proteinase genetic polymorphisms in the development of emphysema

Emphysema is a destructive lung disease that obstructs the airways and compromises oxygen transfer from the lungs to the bloodstream, causing a decrease in respiratory function. More than 1,100 people die of the disease in Canada each year. Currently, there are no treatments to cure emphysema. Cigarette smoking is the major risk factor for developing the disease. Yet only 15 to 20 per cent of smokers develop symptoms. An increase in protein-degrading enzymes called proteinases is believed to play a role in the origin of emphysema. Previous studies also suggest a genetic predisposition to airflow obstruction. Variations in the genes regulating these proteinase enzymes may be responsible for individual differences in response to cigarette smoke. Alison Wallace is researching whether genetic variants in proteinases increase smokers’ susceptibility to emphysema. If so, this information would help identify people at risk for the disease, contributing to early promotion of anti-smoking strategies and possibly leading to new methods for early detection and treatment. In addition, drugs that inhibit proteinases could be targeted to patients predisposed to emphysema, but unable to quit smoking.

Early progression and detection of ovarian cancer

In developed countries, ovarian cancer is the leading cause of death from gynecologic malignancies in women. The five-year survival rate is only 35 to 40 per cent, a rate that hasn’t changed significantly in 25 years. The poor prognosis is due to the lack of a reliable test for early detection and the inability to identify early symptoms of the disease, which means the majority of ovarian tumours are diagnosed at an advanced stage. During progression to malignancy, normal ovarian surface epithelial cells, which give rise to the majority of epithelial ovarian cancers, acquire more complex and highly differentiated characteristics that most often resemble epithelial cells in the fallopian tube and uterus. This change may provide an advantage for growing cancer cells. Michelle Woo is screening ovarian tumour tissues for markers known to be present in the fallopian tube and uterus. She has recently discovered a protein in ovarian tumours that may be an early indicator of ovarian cancer. Another approach she is using to examine early changes in ovarian tumour progression involves the use of a unique three-dimensional culture system to mimic the development of ovarian tumours in women. Michelle hopes this research will identify new predictive markers that can be used for early screening and prevention of ovarian cancer.

Game on: diminishing risks for depressive symptoms in early adolescence through positive involvement in team sports

In early adolescence, both girls and boys report increases in levels of depression. However, by late adolescence the rates of depression among girls are double those found among boys. Research shows that boys and girls’ perceptions about athletic competence (how good they are at sports), social acceptance (how popular they are among peers), and body dissatisfaction (negative feelings about their bodies) are strong predictors of depression. Since girls tend to report lower levels of athletic competence, participate in sports at lower rates, and report higher levels of body dissatisfaction than boys, they may be at greater risk for depression. Erin Boone is examining whether positive involvement in team sports increases perceptions of athletic competence and social acceptance, and helps to diminish body dissatisfaction among both girls and boys. The study will be among the first to assess the mechanisms that link positive team sports involvement to diminished risks for depression in adolescence. Findings will outline the mental health benefits associated with team sports involvement and highlight the need to sustain adolescents’ interest and participation in sports.

Molecular analysis of transplant recipients

One of the major problems for patients who have undergone heart or other transplants is the potential for the body’s own immune system to attack the newly introduced organ. As a result, patients must take large doses of immunosuppressive drugs daily to prevent rejection of the new organ, which the body perceives as foreign. Unfortunately, these medications interfere with normal immune response, which leads to a wide range of dangerous side effects, including higher susceptibility to infections and cancer. Dosage must be carefully monitored: not enough, and the body will begin to reject the organ; too much, and patients must deal with the serious side effects. The goal of Edward Chang’s work is to develop new genetic tests to predict exactly how much medication each individual patient requires to ensure the organ is accepted with minimal side effects.

Identification of genes key to the progression of squamous cell carcinoma of the lung by 3p array comparative genomic hybridization

Lung cancer accounts for the majority of cancer deaths in Canada. Unfortunately, diagnosis typically occurs after lung cancer is well-established, too late for effective treatment. To develop more effective ways of detecting and treating cancer, researchers are studying the genetic makeup of patients, with the goal of identifying and characterizing particular genes that may either suppress or promote the onset and progression of lung cancer. Using an approach that combines laboratory benchwork with bioinformatics techniques (the use of computer tools and databases to analyze large amounts of biological data), Bradley Coe is focusing his work on a specific chromosome, 3p, with which genetic alterations have recently been linked to the development of lung cancer. Identifying genes critical to the disease process will lead to a better overall understanding of lung cancer and may point the way to more targeted diagnostic tests and treatment.

Cellular excitation contraction coupling of intact airway smooth muscle

Diseases of the airways, such as asthma, are often characterized by excessive constriction of tissues caused by the over-contracting of smooth muscle cells. This contraction can severely impair breathing and compromise oxygen exchange between the lungs and blood system. Calcium is a major activator of smooth muscle cell contraction, and the concentration of calcium within cells determines the extent of contraction. Using intact airway muscle tissues, Jiazhen Dai is undertaking an extensive survey of the pattern and the mechanisms of calcium-dependent contraction in both healthy and diseased airways. In particular, she will investigate a newly-uncovered pattern of asynchronous, wave-like calcium oscillation to assess its role in airway constriction. This research will provide a better understanding of the mechanisms of airway constriction and ultimately, new drugs to effectively treat respiratory conditions such as asthma.

Delayed recovery and chronic disability associated with whiplash associated disorders

Whiplash is the most common injury from motor vehicle collisions, and a major cause of chronic disability and pain. The progression and outcome of whiplash treatments vary, as does recovery time. Dr. John Dufton, an experienced chiropractor, is studying factors that lead to delayed recovery in patients with whiplash. Using the nationwide database of CBI Health, Dr. Dufton is comparing patients from BC, Alberta, Saskatchewan, Ontario and Quebec to determine how different types of insurance compensation and litigation systems influence patient recovery. He is also identifying physical factors and patient characteristics that place people at higher risk of developing chronic disability. The findings will provide new data on the factors that affect recovery after a whiplash injury.

Identification of gene regulatory changes involved in cancer progression by gene expression studies and bioinformatic analyses

Obi Griffith was part of a team at the BC Cancer Agency’s Michael Smith Genome Sciences Centre, that cracked the genetic code for Severe Acute Respiratory Syndrome (SARS) in April 2003. In his MSFHR-funded research, Obi is examining how changes in the regulatory sequences of DNA may lead to cancer. By comparing the activation patterns of clusters of genes in normal and cancerous tissue, Obi is working to identify genes that undergo a change in regulation leading to cancer. Once these cancer-causing mutations are identified, he will investigate the biochemical mechanisms responsible for these regulatory changes. Learning more about specific gene regulation changes that lead to cancer may lead to new ways to diagnose, predict and treat cancer using gene-based therapies.

Risk-benefit tradeoffs: A community-based risk assessment of sulfuric emissions from five Canadian petroleum refineries producing reduced sulfur gasoline

In 1999, the federal government announced that oil companies will need to reduce the sulfur content of gasoline from 360 parts per million (ppm) to 30 ppm by January 2005. As a result, refineries across the country will be required to remove more sulfur from the crude oil they process, possibly resulting in higher concentrations of sulfur in their stack emissions. While this regulation is intended to protect Canadians from harmful compounds in tailpipe exhaust, communities close to oil refineries may be exposed to higher concentrations of those same compounds. Using air pollution and population data from five major Canadian refinery communities, Sarah Henderson is assessing the potential for sulfuric emissions from refineries to affect public health, and is determining how federal gas regulations could increase that potential. She hopes the research will lead to a model that policy makers can use to quantify how sources of air pollution can affect the health of surrounding communities.