Defining the role of FoxP3 in human CD4+CD25+ T regulatory cells

In the last few decades, new immunosuppressive drugs have improved our ability to treat autoimmune diseases and perform successful transplantation procedures. Despite the success of these drugs, serious side effects including generalized immunosuppression, infections, cancers, diabetes and seizures considerably decrease patients’ quality of life. Recent research in this area has focussed on T regulatory (Tr) cells, a recently characterized subset of white blood cells that have the ability to suppress undesired immune responses, while leaving other aspects of the normal immune system intact. Sarah Allan’s research addresses questions about the molecular and cellular biology of Tr cells. She is investigating how Tr cells arise naturally, the mechanisms by which they suppress immune responses, and how they differ from other types of T cells at the molecular and genetic level. Ultimately, her work will contribute to the development of novel therapies for autoimmune diseases, transplantation, and other pathologies of the immune system.

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.

Synaptic protein dysfunction in neurodevelopmental disorders: The role of PDS-95 and neuroligin in Fragile X syndrome and autism

It is known that neurodevelopmental disorders such as Fragile-X Syndrome and autism have a strong genetic basis, yet the genes involved have not been clearly identified. Both disorders exhibit patterns indicative of abnormal or halted synaptic development (formation of the junction between neurons). Research indicates that these synaptic abnormalities may be the underlying neurological cause of these disorders. Genetic analyses of individuals with Fragile-x and autism revealed genes, and their proteins, thought to be involved in synapse formation and maintenance but the exact neurological mechanisms that lead to these diseases remain unknown. Rochelle Bruneau aims to clarify the role of the specific proteins involved in synapse development, testing for their implication in Fragile-X Syndrome and autism. She will study proteins involved in both the formation and function of synapses and hopes to examine potential therapeutic proteins for reducing the severity or preventing the onset of symptoms of neurodevelopmental disorders.

Identification of predictive drug response signatures by whole genome profiling of lung tumors

Non-small cell lung cancer (NSCLC) accounts for an estimated 80% of known lung cancer cases. In many instances, these tumors are inoperable by the time of diagnosis, leaving chemotherapy as the main option for treatment. Unfortunately, tumor response to chemotherapy can vary and the presence of even a few drug-resistant cells within a tumor may result in disease recurrence as these cells expand to form a new tumor mass. Using archived NSCLC tumour samples, Timon Buys is working to identify genomic “signatures” that might predict how well or poorly a drug will act to destroy tumour tissues. First, he is using a technology called array comparative genomic hybridization, which allows researchers to assess changes in gene copy number throughout the whole human genome. Second, isolated patient cancer tissue will be grown and treated in mice to preview how a specific case will behave after treatment with chemotherapy drugs. Information from these studies could point to ways to effectively eliminate tumor recurrence due to drug resistance, helping to improve the prospects of patient survival.

Activation of notch signaling pathway in the vasculature

Endothelial cells are a thin layer of cells that line blood and lymph vessels. They play a number of essential and complex roles within the body including acting as a selective barrier to the passage of molecules and cells between the blood and the surrounding bodily tissue. Angiogenesis, the process in which new vessels grow from original vessels, requires endothelial cell growth. Angiogenesis occurs in physiological processes such as wound-healing and menstruation. Malfunctions in angiogenesis – when new blood vessels either grow excessively or insufficiently – can result in serious diseases such as cancer, rheumatoid arthritis, coronary heart disease and stroke. Linda Ya-Ting Chang is studying the mechanism that controls endothelial growth and differentiation – the Notch signalling pathway. By blocking endogenous (originating internally) Notch signaling, she is investigating the response of endothelial cells to stress-induced programmed cell death (apoptosis). Linda is also studying the molecular interactions between the two components of the Notch pathway (the receptors and the ligands) during programmed cell death to determine the important molecular players in the process. The results from Linda’s research will enhance understanding of the process of angiogenesis and may lead to new therapeutic methods for vascular-related diseases.

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.

Nuclear import of minute virus of mice

A technology that shows great promise in treating human disease is the use of viruses as vectors (or carriers) to insert and replicate new genetic material into the genome of a diseased cell. Parvoviruses are suitable candidates for use as vectors, including the parvovirus known as MVM (minute virus of mice). These viruses have been successfully tested in many preclinical models of human diseases, including cancer. As part of its replication cycle, the genome of MVM must enter the nucleus of its host cell. How MVM accomplishes this is unknown, but studies suggest that the way it breaches the nuclear membrane is unlike that of any other known virus. Sarah Cohen is using electron microscopy, combined with biochemical and genetic approaches, to investigate the mechanisms employed by MVM to enter the nucleus of a host cell. Gaining a more developed understanding of these entry mechanisms will aid in the development of MVM as a therapeutic vector, helping to bring MVM-based vectors into clinical trials. A successful vector for gene therapy could ultimately deliver healthy genes to patients for the treatment of a wide variety of genetic diseases.

Chemokine processing by matrix metalloproteinases

Chemokines are small proteins that direct the migration of white blood cells (including T cells) in the body. This process is very important in mounting an immune response against invading pathogens. Chemokine function is known to be implicated in autoimmune diseases such as multiple sclerosis and graft versus host disease, and has recently been linked to the ability of cancer to spread from one part of the body to others. Jennifer Cox is investigating the ability of a family of proteases to process and alter chemokine activity. Focusing on a group known as matrix metalloproteinases, she has uncovered that one of these proteases cleaves specific chemokines, altering their ability to induce the migration of T cells. Now, she hopes to use mouse models to prove that this interaction is relevant in the body. These studies will result in a better understanding of immune regulation at a molecular level and could have implications for the prevention of cancer spread and the treatment of autoimmune diseases.

Global versus local processing in Balint's Syndrome

Balint’s syndrome is a rare disorder usually caused by brain injury to both sides of the parietal lobe following a stroke. This region of the brain is involved in cognition, information processing, spatial orientation, and sensations of pain and touch. People with Balint’s are unable to pay attention to more than one object at a time, experience spatial difficulty locating objects, and have trouble accurately reaching for objects. While there is a lack of research into these complex symptoms, preliminary research suggests these patients focus on the “local” elements of an object, instead of the “global” whole. For example, they may not see 🙂 as a smiling happy-face icon, but as a colon, dash or bracket. Kirsten Dalrymple is studying how Balint’s patients perceive objects by presenting them with stimuli such as the happy-face icon that can be perceived globally or locally. This research could result in rehabilitation strategies to improve patients’ ability to perceive everyday objects as others perceive them, which will improve their quality of life and ability to function normally.

The role of genomic DNA methylation in the clonal evolution of cancer cells

Under normal circumstances, cells are prevented from dividing uncontrollably by the presence of tumour suppressor genes (TSGs). In order for cancers to grow, these genes must be turned off, either by DNA mutations or by a process called methylation. Methylation turns TSGs off with the introduction of small chemical “tags”, which prompt the cell to fold up the gene and make its DNA blueprint unreadable. This process is reversible, and certain drugs have been shown to remove methyl tags from DNA. Jonathan Davies’ research focuses on developing techniques to identify the TSGs in lung cancer genomes that may be frequently turned off by the methylation process. He hopes to determine the DNA methylation patterns of cells making up lung tumours and identify potential drug targets. If TSGs can be reactivated with de-methylating drugs, it could provide a new treatment option for halting or eliminating the growth of tumours, leading to better care and increased recovery rates for lung cancer patients.