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.

Informed Decision Making: The Interaction Between Sustainable Maternity Care Services and Community Sustainability

To examine the role of maternity care in the sustainability of rural and remote communities, with the goal of assisting decision-makers in understanding the implications for the community and to provide them with a framework for making challenging decisions involving changes to the provision of these and other health services.

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An investigation into priority setting by hospital formulary committees in British Columbia: what weight does evidence carry in the face of competing factors?

Some health care services are prioritized at the expense of others, due to limited resources. Many decision makers set priorities for allocating resources based on evidence derived through health economics and clinical research. The trend towards evidence-informed health policies has gained considerable momentum in Canada, particularly with pharmaceutical policy because drugs are a major cost driver in the health system. It is clear, however, that health policies are not determined solely on the basis of health research evidence. Kristy Armstrong is examining the roles played by evidence and other factors — such as an institution’s values, and the interests of key stakeholders — during decision making about drug coverage in both a regional health authority and a hospital in British Columbia. This study will help clarify the environment in which health policy is set and potentially point to ways of more effectively integrating use of evidence in decision making.

The role of protein tyrosine phosphatase alpha (PTPa) in integrin signaling in fibroblasts

Communication between the outside and inside of cells relies on protein molecules (such as integrins) at the cell surface, which interact with the external environment and send signals to other molecules inside the cell. These molecules interact to form complex signaling cascades to effect appropriate cell responses. Protein tyrosine phosphatases (PTPs) are a family of proteins that play a critical role in cell signaling processes. Shirley Chen is investigating the function of PTPalpha, an important player in integrin signaling. This signaling pathway regulates cell growth, migration, and survival, and has been implicated in cancer development and progression. By studying the activity of PTPalpha-deficient cells in comparison to normal cells, she will learn more about the role of this protein in the integrin signaling cascade. Since integrin signaling governs several aspects of how a cell responds to the environment, her study of this process will help reveal why certain cells, such as cancer cells, behave abnormally. In the long term, her research could contribute to understanding the onset and course of diseases such as cancer and diabetes, and may potentially lead to PTPalpha-based therapeutics for these diseases.

The identification of susceptibility genes and phenotypic subgroups for autism spectrum disorders

Autism Spectrum Disorders (ASDs) are characterized by impairments in social interaction and communication, as well as restrictive behaviours and interests. These life-long disabilities affect more than 1 in 250 individuals. It has been shown that early diagnosis is essential for children with ASD: the earlier intervention is initiated, the better the outcome. However, affected children are commonly not definitively diagnosed until they are three years of age or older. Sibling, twin and family studies have shown that ASDs are largely genetic in origin and certain chromosomal regions harbouring possible ASD susceptibility genes have been identified. Recent studies suggest that between 5 and 48% of individuals with autism exhibit chromosomal anomalies. This suggests that small chromosomal anomalies, such as microdeletions and microduplications, may be relatively common and clinically important markers for identifying underlying causes of, and susceptible gene regions for, ASDs. Dr. Suzanne Lewis is researching the genetic susceptibilities of ASD, using a novel method for the analysis of regional changes in DNA called microarray-based comparative genomic hybridization (array-CGH). Using this method she is identifying and characterizing chromosomal abnormalities in 100 subjects with ASD. In parallel, Dr. Lewis is also researching ASD phenotypes – genetic influences in combination with respective behavioural, physical, medical, environmental and family findings. Dr. Lewis aims to build a research pathway that identifies genetically distinct subgroups of ASD that also share unique clinical phenotypes. Through researching this genotype/phenotype correlation Dr. Lewis ultimately hopes her research will contribute to a better understanding of the genetic causes and consequences of autism and help in developing methods for the very early identification of infants and families at risk for autism.

In silico approaches for investigating mechanisms of gene regulation

More than 95% of the human genome is made up of non-coding DNA, historically dismissed as ‘junk DNA’ of unknown function. It is now known that the so-called junk DNA isn’t junk at all; in fact, it contains important information specifying how genes are regulated. Non-coding DNA sequences located adjacent to genes typically contain binding sites for proteins that act like regulatory switches, turning genes on or off in the appropriate cell types and under particular conditions. Errors in this process have been linked to diseases ranging from cancer to obesity. Recent studies have determined that there are a surprisingly large number of non-coding sequences that are highly conserved across the vertebrate lineage. These regions, termed ‘ultraconserved sequences’, are almost identical in humans, rodents and fish. They have been minimally explored but appear to have an important role in regulating the expression of key developmental genes. Shannan Ho Sui is studying the properties of ultraconserved regions in the human genome to assess their potential role in gene regulation. Her research involves using bioinformatics techniques to find and analyze patterns in DNA sequences. By determining the properties of genes associated with ultraconserved regions, evaluating how frequently recombination occurs in these regions, and locating similarly highly conserved non-coding sequences in the fly and worm genomes, Shannan hopes to develop a model describing how and why these regions are maintained in the genome. Her research results will provide valuable insights into mechanisms of gene regulation that play important roles in development and disease.

Palmitoylation of ABCA1 and its effect on localization and function

Atherosclerosis is a slow, progressive disease caused by the buildup of plaque (fatty substances, cholesterol, cellular waste products, calcium and other substances) in the inner lining of the arteries. This plaque buildup can lead to heart attack, stroke or gangrene. Research has shown that high-density lipoproteins (HDL) remove excess cholesterol from plaque by transporting cholesterol away from the arteries and back to the liver, thus slowing the buildup. Higher levels of HDL seem to be protective against coronary artery disease, and thus HDL is sometimes referred to as “”good”” cholesterol. Dr. Roshni Singaraja is researching the role of the newly-discovered gene ABCA1, whose function is to to produce HDL. Specifically, she is investigating the role of the palmitoylation process (the attachment of palmitate – fatty acids – to proteins which acts as a signal for the protein to be transported) on ABCA1 and its function. In addition, Roshni will examine the function of ABCA1 in the brain and the impact of palmitoylation on these functions. Roshni’s research may lead to potential strategies to increase HDL production and to accelerate or reverse cholesterol transport in order to prevent atherosclerosis.

The American Society of Addiction Medicine – patient placement criteria, second edition revised (PPC- 2R) validity study in Canadian women

Mental health and addiction services have experienced frequent budget cuts in recent years, as governments try to contain health care spending. Yet, as Dr. Shimi Kang discovered during her earlier research at the World Health Organization in Geneva, Switzerland, substance use and mental illness are major global public health issues. The American Society of Addiction Medicine (ASAM) has developed a software program for making treatment decisions that consider resource issues. The program prompts interviewers to ask a series of questions, and produces recommendations for matching patients to the most appropriate treatment setting, based on standardized criteria. The software is now widely used in the United States, and studied in several other countries. However, the effectiveness of this assessment tool has never been studied within the Canadian health care system or with women, who experience different rates of addictive disorders and mental illness than men. Shimi is conducting the first Canadian study to evaluate whether the program can be applied to assess the complex biological, psychological and social needs of women with mental health and addiction problems. The results may lead to better techniques for treating drug and alcohol addiction and preventing relapse in women.