Source, Target and Biological Role of 14-3-3 Proteins in Rheumatoid Arthritis

Rheumatoid arthritis (RA) is the most common autoimmune disease worldwide and affects ~1% of Canadians. Its chronic inflammation causes pain and joint failure, eventually leading to disfiguration and disability. The cartilage and bone destruction of RA is thought to be caused by a certain family of enzymes, MMPs, that are capable of breaking down all joint components, causing severe damage and pain. Recently, 14-3-3 proteins were discovered to be critical communication proteins between skin cells during the healing process. 14-3-3 proteins also stimulate production of MMPs. Thus, the abnormally high amounts of 14-3-3 found in RA joints might be responsible for excess MMPs production, which leads to joint destruction. Jennifer is studying how 14-3-3 proteins may stimulate production of MMPs and lead to the joint destruction in RA. Ultimately, her work will contribute to the development of novel therapeutic strategies to diagnose and treat RA and other arthritic diseases.

Dying for choices: decision-making in end-of-life care

Every year more than 185,000 Canadians die in acute-care settings. Previous research has shown that patient choices regarding care are extensively influenced by factors inherent in the place of death. However, no Canadian research has examined how end-of-life care (EOLC) decisions are influenced and shaped through these factors. The focus of Marian Krawczyk’s research is to examine EOLC decision-making within acute-care settings, specifically in regards to the use of life-extending technologies. Her study examines factors that are overlooked in existing research including the location of communication when discussing EOLC options, differing medical models of palliative care, doctor-patient communication, and the social capital and economic resources of patients. By providing data that examines communication in EOLC in British Columbia, this research seeks to strengthen the ability of health care providers, patients and families to effectively communicate and negotiate patient care choices before and during acute care settings. The research will also increase the ability and efficiency of policy makers in the delivery and distribution of health services. Finally, it may help improve communication and decrease consumer-driven health costs.

Physical Activity, Local Joint Factors and Osteoarthritis

Osteoarthritis is a leading cause of disability in Canada. This type of arthritis causes deterioration in the joints, leading to swelling, pain and stiffness. It often results in lost work time and places limits on an individual’s normal function and recreational activity. Both the increasing prevalence of osteoarthritis in the province’s aging population, and the lengthy surgical wait times for replacing osteoarthritic joints are high profile health care issues in British Columbia. Physical activity can offer almost universal improvements in health, which includes decreasing the risk of heart disease, stroke, high blood pressure and cancer. Health Canada recommends all adults participate in at least 30 minutes of moderate-intensity exercise most days. But some types or too much physical activity, such as competitive sports or heavy physical work, can cause excessive wear and tear in the joints, increasing the risk of osteoarthritis. In addition, some people may be more vulnerable to the type or amount of physical activity because of the way their legs are aligned (e.g. bow-legged) and/or because of increased flexibility (hypermobility). Chuck Ratzlaff is comparing data on lifetime physical activity and these joint factors in people with knee and hip osteoarthritis to those who don’t have the condition, as part of a national arthritis study. The results can be used to recommend appropriate amounts and types of physical activities that may decrease the risk of osteoarthritis of the hip and knee.

Cognitive and behavioural characterization of individuals genetically at risk for frontotemporal dementia

Frontotemporal dementia (FTD) is the second most common form of dementia affecting individuals under the age of 65. Characterized by the gradual wasting away of the brain’s frontal and anterior temporal lobes, FTD progressively affects mental function, personality and behaviour, while leaving memory largely intact. Over time, they lose the ability to organize and plan, become emotionally blunted and socially inappropriate, lose insight on the impact of their behaviour, and experience difficulty with speech and language. Currently, there is no cure for FTD and treatment methods are limited. Vulnerability to some forms of FTD has been linked to a specific gene mutation that runs in families. While the symptoms of FTD are well documented, few studies have looked at the characteristics of individuals who carry the mutation but do not yet show obvious FTD symptoms. However, research shows that even when they do not exhibit obvious symptoms of FTD, individuals who carry the gene mutation perform significantly worse on tests that measure frontal lobe functioning than family members who do not carry the mutated gene. Using measures such as cognitive testing, behavioural questionnaires and brain imaging, Amanda LaMarre is seeking to establish clinical markers of FTD in genetically at risk individuals in order to identify and distinguish the earliest symptoms. She hopes that by gaining a better understanding of the development and onset of FTD, her research will provide a base for future research aimed at preventing or slowing the progression of the disease.

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.

Entry of Dendritic Cells into the Brain: Regulation by Endothelial Cell Adhesion Molecules and Chemokines

Immune reactions in the central nervous system (CNS) – the brain and spinal cord – differ from other organs. Under normal conditions, the endothelial cells lining blood vessels in the brain act as a “blood-brain barrier” to block the entry of most immune cells into the CNS. In some CNS diseases like multiple sclerosis, and in trauma, stroke and infections, this barrier is compromised. As a result, immune cells migrate to the brain in large numbers causing inflammation, which can lead to serious consequences. Azadeh Arjmandi is studying how immune cells gain access to the brain and spinal cord in infectious, inflammatory and autoimmune diseases. Immune cells called dendritic cells have been found in the central nervous systems of patients with these diseases and their numbers increase with more chronic conditions. Azadeh is examining dendritic cell trafficking across the blood-brain barrier in order to further characterize the molecular mechanisms of inflammation in the brain. This will provide important information about how certain CNS diseases develop and may contribute to more effective treatments.

Meiotic errors in spermatogenesis: the role of recombination and synapsis in male-infertility and the production of aneuploid sperm

About two per cent of men are infertile due to defects in sperm production. In most cases, the underlying cause is unknown. During sperm production, two similar chromosomes – microscopic bodies that carry heredity DNA – pair up and exchange genetic material in a process called meiotic recombination. Recent studies have shown that recombination rates are significantly reduced in infertile men. Infertile men are also more likely to produce sperm with extra or missing chromosomes (called aneuploid sperm). This aneuploid abnormality is the most frequent cause of miscarriage, and among live births, the most common cause of congenital malformations. Kyle Ferguson is using leading edge technology to determine if and how aberrant recombination causes infertility. He is also investigating the recombination patterns that lead to production of aneuploid sperm. This information will help identify genetic mutations that contribute to male infertility, and may lead to new therapies for the condition.

Death anxiety and spousal caregiving of persons with dementia

Persons with a dementing illness such as Alzheimer disease are often cared for at home by family members. Caring for someone with Alzheimer disease can be a stressful and challenging experience. Death anxiety (the fear of death or the dying process) is one issue that has received little attention in research on family caregivers of persons with dementia. As a person with Alzheimer disease may die within years of receiving this diagnosis, a family member may experience death anxiety through fear of watching the person they care for die, or fear of dying while the person with dementia still needs their support. Anthony Kupferschmidt is seeking to understand the degree to which family caregivers of persons with dementia experience feelings of death anxiety and the effect of these fears on their health and ability to cope and continue in their caregiving role. Findings from this research could ultimately contribute to improvements in education and other community-level programs to better support caregivers of persons with a terminal diagnosis. Anthony is also the 2006 recipient of the Canadian Association on Gerentology Margery Boyce Bursary. This award supports post-baccalaureate students who have made a significant contribution to their community through volunteer activities with or on behalf of seniors and who are registered in a program of study focused on aging or the aged. This prestigious award is the only national award available to gerontology graduate students that is not granted on the basis of financial need.

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 the effect of T regulatory cells on B cell proliferation and immunoglobin production and isotype switching

A growing field in the world of immunology is the study of T regulatory cells (Tregs), a specialized subset of T cells that has the ability to “”turn off”” the immune system after an infection has been cleared. While research has been focused on how Tregs suppress one class of lymphocytes (Th1 and Th2 cells) from proliferating and making molecules that are involved in activating the immune system, the effect of Tregs on the other major class of lymphocytes – the B cells – has received far less attention. Previous experimentation in the laboratory of Grace Lam’s supervisor, Dr. Anthony Chow, has revealed that one injection of Toxic Shock Syndrome Toxin (TSST-1) to cell cultures induces a massive systemic inflammatory response. However, repeated injections of this toxin leads to the activation of Tregs that “”calm down”” the immune response. Grace’s own research has shown that TSST-1 induced Tregs may be able to prevent activation of B cells by suppressing B cell proliferation and/or inducing B cell death. Now, she is studying the mechanisms by which this down regulation occurs. This work holds important promise for understanding and developing more effective treatment for chronic health problems caused by an overactive immune response. Diseases such as systemic sclerosis, systemic lupus erythematosus, or rheumatoid arthritis, all result from overactive B cells producing excessive amounts of antibodies that damage normal tissue. Grace hopes her research might open the possibility of employing TSST-1 induced Tregs to shut down this abnormal immune response.