Chromosomal instability is a hallmark of tumour cells in human cancer. Regions of chromosomal instability can have various forms including single point mutations, rearrangements, whole chromosome loss or duplication, or chromosomal segments containing DNA copy number change. The alterations change the expression of cellular constituents and eventually result in cells that do not function normally. Finding regions of chromosomal instability provides important locations in the human genome that are both symptomatic and diagnostic markers of various cancers. Recently developed techniques called array comparative genomic hybridization (aCGH) have allowed scientists an unprecedented high degree of resolution to detect regions of chromosomal instability in cancer patients. The experiments produce both a high volume of data and noisy signals that are not cleanly interpretable. Therefore, robust computational techniques must be developed that can automatically identify regions of chromosomal instability. Sohrab Shah is developing computational methods and statistical models that, given aCGH data for one or more patients, can accurately and reliably detect chromosomal aberrations. His research will first evaluate this method on standard data sets where the location of the aberrations are known, and then apply the method to three large scale genomic studies to discover chromosomal locations affected in lung, brain and lymphoma tumours. He will also assess the diagnostic utility of chromosomal alterations that are recurrent across patients and develop prototype diagnostic tests that may ultimately be put into clinical practice.
Year: 2006
ACK family tyrosine kinase may participate in the control of dorsal closure through negative regulation of Egfr
The Rho family of small GTPases in the fruit fly Drosophila are key controllers of cell shape and cell movement through their participation in signalling networks that control a variety of cellular processes. These proteins function as molecular “switches”, turning on or off the particular steps in the signal pathways to control cell shape or cell movement. The study of these molecules provides us with important medical insight since disturbance of their signalling has been implicated in a variety of disorders including cancer and a number of inherited conditions, such as mental retardation, deafness and facial deformities. These proteins have also been shown to be key regulators in wound healing. The activated Cdc42 kinases (ACKs) are proteins shown to be effectors for the Rho GTPases Cdc42, and are linked to the regulation of Drosophila Dorsal Closure (DC). DC is a well-known animal model system for studying wound healing. Previous studies have demonstrated Drosophila activated Cdc42 kinase (DACK) functions in controlling cell shape change and movement of epidermal cells during DC. Weiping Shen is using the DC as a model system to assemble signalling networks controlling the movement and shape of cells. The learning gained from these signalling pathways will shed light on their roles in human development and disease. By developing a better understanding of the mechanisms that allow signals to translate into physical movements, this research could lead ultimately to solving many genetic and developmental puzzles related to human diseases.
Improved Biostatistical Methods to Detect Gene-by-Environment Interaction in Case Control Association Studies
Complex genetic diseases are thought to result from genetic susceptibility factors acting in conjunction with environmental, lifestyle or non-genetic factors such as infectious, chemical, physical, nutritional and behavioural exposures. In the past, researchers have used the case-control study design to investigate disease associations with non-genetic factors. Recently, new genetic information in the form of Single Nucleotide Polymorphisms (SNPs) has been integrated into these population health studies in an attempt to better understand the joint effects of non-genetic and genetic risk factors. However, conventional statistical methods for this study design are not powerful enough to detect such joint effects, even for studies with very large sample sizes. Jihyung Shin is developing new biostatistical methods to more efficiently extract information from case-control data about statistical interactions between genetic and non-genetic risk factors for disease. By developing extensions of the methodology to allow for missing information on genetic risk factors in a statistically valid way, her work can accommodate the analysis of disease associations with SNP haplotypes, which are combinations of genetic variants at several nearby SNPs on the same chromosome. This type of analysis can offer improved power over analysis of single SNPs for detecting the effects of genetic factors and their interactions with non-genetic risk factors. The ability to identify interactions between genes and non-genetic factors that affect the risks of complex genetic disorders will improve our understanding of disease pathogenesis and help with the development of more effective and appropriate treatments, prevention and screening tools.
An examination of injection drug use sites: the influence of social and physical context on drug-related harms and public health interventions
Injection drug use may result in severe health consequences including increased risk of viral infections such as HIV and hepatitis C, soft tissue infections, and drug overdose. Recently, with increasing attention being paid to the impact of environment on individual and public health, intervention efforts for injection drug users (IDUs) have moved beyond the modification of individual behaviour and focused on modifying the environments in which people use injection drugs. One recent and controversial example of this involves medically supervised injection facilities, where IDUs can inject pre-obtained illicit drugs under the supervision of health care professionals. William Small is studying and comparing three types of injecting settings in the Downtown Eastside: private injecting spaces (such as homes), public injecting spaces (such as alleys), and Vancouver’s supervised injecting facility. He is examining how the social and physical context of each setting influences the ability of injection drug users to employ HIV-prevention measures and safer injection practices. The findings of this research will build important knowledge about the health and HIV vulnerabilities of IDUs in the Downtown Eastside. Also, this research will provide information on the impact of current interventions, which may inform future interventions for addressing injection drug use.
Pharmacogenetics of Mycophenolate in Thoracic Transplant Recipients: Role of UDP-Glucuronosyltransferase Genetic Polymorphisms
Thoracic (heart and/or lung) transplantation is an effective but aggressive measure for treatment of end-stage heart and lung diseases. However, rejection of the transplanted organ remains a major problem and frequently leads to organ loss and death. All transplant recipients take immunosuppressants (drugs that prevent rejection), yet over-immunosuppression exposes them to undesirable infections and other side effects. Mycophenolic acid (MPA) is an effective immunosuppressant commonly used in transplantation. However, tailoring MPA therapy is challenging due to the wide variability and unpredictability in treatment responsiveness and side effects among patients. Genetic makeup and metabolism of MPA have a significant bearing on drug responsiveness. While many studies provide better understanding of MPA in kidney transplant recipients, information on the thoracic transplant population is scarce. Lillian Ting’s research is exploring the role of genetics in determining treatment responses. The ultimate goal is to individualize regimens, even before treatment begins, for each patient in order to obtain optimal treatment response and minimal toxicity. The results from Lillian’s study will add valuable knowledge to transplantation management. It will be directly incorporated into patient care, improving patient survival and quality of life after transplantation.
Effect of cholesterol on prohormone processing in pancreatic beta cells in Type 2 Diabetes Mellitus
Type 2 diabetes mellitus is a devastating chronic disease affecting close to two million Canadians. The disease is characterized by a loss of insulin action in tissues such as muscle and a loss of insulin secretion by the islet beta cells of the pancreas. The number of beta cells within the pancreas – an important determinant of the amount of insulin secreted – is decreased in persons with type 2 diabetes. This supports the idea that the progressive loss of insulin secretion in this disease is due to a loss of functional beta cells. The loss of beta cells is associated with the formation of toxic islet amyloid deposits, consisting primarily of the beta cell peptide islet amyloid polypeptide (IAPP or amylin). Although the mechanism underlying islet amyloid formation is not known, impaired processing of the IAPP precursor, proIAPP, has been proposed to be an important initiating event. In type 2 diabetes, elevated glucose and free fatty acids can cause beta cell dysfunction, which raises the question whether elevated cholesterol induces beta cell dysfunction in this disease. Zainisha Vasanji’s research is aimed at determining whether exposure of beta cells to elevated cholesterol is the trigger for the chain of events that lead to islet amyloid formation in type 2 diabetes. Zainisha’s study may help delineate the cause of the beta cell defect in type 2 diabetes and may lead to new therapies to prevent the progressive loss of insulin secretion in this disease.
New RNAs Phenotypes from Old by Random Recombination and Selection
The emergence of new viral species or strains by evolution is viewed as a great potential danger to human health. Besides mutation, recombination (shuffling of genes) plays an important role in the evolution of viruses – such as HIV or Hepatitis E. There is significant concern that more dangerous viral strains or species may evolve through recombination. However, the complexity of virus-host systems makes the study of this process very difficult. Using a new method she developed, Qing (Sunny) Wang is using ribozymes (specific functional RNAs) as a model for studying the mechanisms of random recombination in viruses. She hopes that this work will shed more light on how viruses evolve through recombination.
Exposure to polybrominated diphenyl ether (PBDE) flame retardants and thyroid effects in pregnant women
Polybrominated diphenyl ethers (PBDEs) are chemical flame retardants used in furniture foams, certain textiles and many plastics. In Vancouver, PBDE levels in human breast milk increased by about 15 fold from 1992 to 2002, bringing current levels to among the highest reported in the world. While the human health effects from ambient PBDE exposure are unknown, animal and laboratory studies indicate that PBDEs alter the levels and transport of thyroid hormones. This is of particular concern during pregnancy, when thyroid hormones play a critical role in fetal brain development. Because even small changes in maternal thyroid hormone levels in early pregnancy have been linked to neurological deficits in children, the thyroid disrupting potential of PBDEs is of interest for public health. Glenys Webster’s study is examining the relationships between PBDEs and thyroid hormones in 150 pregnant women in Vancouver. Using blood tests, her work will determine whether PDBEs are associated with altered thyroid hormone levels at different stages of pregnancy. A detailed questionnaire will also be used to identify the main sources of maternal exposure to PBDEs. Ultimately, Glenys’ research may lay the foundation for future investigations of PBDEs, other environmental toxins and neurological development in children in Vancouver.
Antibiotic Resistance in Superbugs: Regulation of the Blar beta-lactam sensor of MRSA and the MexAB-OprM multidrug-efflux effector PA3719 from Pseudomonas aeruginosa
Every year, Canada spends hundreds of millions of dollars in the fight against antibiotic-resistant “superbugs”, bacteria that have evolved to outmaneuver the drugs that are designed to kill them. The elaborate resistance machinery that bacteria have developed can be energy consuming for the organism to construct and maintain, so bacteria will activate this defense system only in the presence of antibiotics. This effect is seen within superbugs that are resistant to beta-lactam antibiotics such as penicillin. Mark Wilke is working to understand the regulatory machinery bacteria use to switch on beta-lactam resistance, specifically within the notorious superbugs MRSA (methicillin-resistant Staphylococcus aureus) and Pseudomonas aeruginosa. He is using a technique called X-ray crystallography, which generates atomic resolution “snapshots” of proteins and other molecules in action. His findings could lead to new strategies for combating superbug infections.
Economic studies in BC seniors at high risk of injurious falls
Falling and fall-related injuries are a major health concern for the elderly. It is estimated that 40 per cent of people over age 75 will experience a fall at least once per year. This is a health issue with significant costs to the healthcare system, and to the elderly population. Fall prevention programs exist; however, research and evidence on the cost-effectiveness of these programs is lacking in Canada. The analysis of the costs and cost effectiveness of health technologies is becoming an increasingly important issue in healthcare decision-making. If economic evaluations are missing, decision-makers will lack an important aspect for fully informed decision-making. John Woolcott is conducting one of the first Canadian-based costing assessments of the impact of falls and is investigating the cost effectiveness of fall prevention programs. John is determining the direct and indirect costs of injurious falls in BC and evaluating the cost-effectiveness of existing interventions currently in place to reduce seniors’ falls. He is also focusing his research on how injurious falls affect the quality of life of 400 seniors in BC. John’s research will further educate the health care community regarding the substantial costs of falls and will further inform decision-makers regarding cost-effective interventions.