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.
Program: Trainee
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.
Understanding social competence in Autism Spectrum Disorders: The development of a standardized measure
Autism and its related disorders are commonly described as lying along a continuum that ranges from mild to severe. As a whole, these disorders are often referred to as Autism Spectrum Disorders (ASD). ASD describes individuals who have three main areas of difficulty: communication and language; social interactions; and restricted or repetitive behaviours/interests. Although social difficulties represent the primary problem for higher functioning youth with ASD, there is a lack of standardized measures to assess the nature and severity of their social impairment. In British Columbia, it is particularly important that clinicians have access to standardized and psychometrically sound tools because ASD diagnoses are tied to publicly-funded services. Jodi Yager is developing and validating a measure of social competence that will be appropriate for use with higher functioning individuals with ASD. She anticipates this tool will ultimately be useful to mental health professionals in both clinical practice and research. Jodi’s standardized measure may play a role in assisting with important assessment and diagnostic procedures and in evaluating the effectiveness of interventions and programs (e.g. social skills training). In addition, by providing a detailed assessment of social strengths and weaknesses, this measure could prove helpful in treatment planning, such as recommending services and interventions that are specifically tailored to meet an individual’s needs. By improving our understanding and measurement of social functioning in youth with ASD, Jodi’s research will contribute to improving developmental outcomes and quality of life in this population.
Novel redox-elimination mechanism of enzymatic glycoside hydrolysis: A detailed study of Family 4 glycosidases
Carbohydrates are found in every facet of life, not only in metabolic pathways, but also as key mediators in intercellular communication and cellular activity. Associated with these important biomolecules are a class of enzymes—glycosidases—that contribute to the breakdown of carbohydrates, allowing for their use as an energy source by the cell. Interruption of these processes can affect cell growth by limiting the supply of available nutrients. With more than 90 different known glycosidase families, the recently-discovered Family 4 glycosidases have been shown to operate through a different mechanism. In addition, this family exists in a number of bacteria, but not in mammals. Continuing in research that was previously funded by MSFHR, Vivian Yip is performing a detailed investigation of the mechanisms of Family 4 glycosidases. Ultimately, she is interested in exploring how inhibition of these glycosidases could be used to develop antibiotics that selectively compromise bacteria, but not the host.
Mining the genome and transcriptome of lung cancer for clinically relevant molecular signatures
Lung cancer is responsible for the greatest number of cancer deaths in Canada. Current chemotherapy treatments are largely palliative, and only a small percentage of patients show a favourable response. Like other cancers, the progression of lung tumours is driven by a series of genetic alterations that can vary significantly between patients. The specific set of changes that occur in any individual tumour influences not only its aggressiveness and outcome, but also the effectiveness of cancer treatment. Scott Zuyderduyn will determine the genetic changes in several hundred lung tumour samples for which treatment and outcome is known. He will then employ computational and statistical approaches to determine which changes can accurately predict how a tumour will respond to different treatments. This research has important implications for determining, at diagnosis, the best choice of cancer-fighting treatment.
Coping with Rheumatoid Arthritis: The Effect of Psychosocial Factors on Chronic Pain
Rheumatoid arthritis (RA) is an incurable disease that affects approximately 1 per cent of the western population. It is associated with a variety of symptoms including chronic pain, stiffness and inflammation of joints, fatigue, and frequent mood changes. Because there is no cure, treatment focuses on alleviating symptoms and maintaining mobility and function. Disease factors only partially predict pain and disability among RA patients; consequently, there is growing interest in the influence of psychological and social factors on the progression of this disease. Amy Zwicker is examining the role and degree to which social support from friends and family, and effective coping strategies may help to decrease pain and increase functional ability in people living with RA. She is also examining the effects of these psychosocial factors on mood and physical well-being of patients and their spouses. Findings from her research may contribute to the development psychologically-based interventions that help RA patients deal more effectively with the pain and disability associated with the disease.