Transplantation is the treatment of choice for many forms of end-stage organ failure and cancers of the immune system. Due to the difficulty in finding fully compatible donors, the patient’s immune system must be suppressed with drugs to prevent it from rejecting the transplanted tissue. While necessary, these drugs suppress all immune response, causing serious side effects including increased risk for infections, cancers, damage to kidneys, hypertension, diabetes and seizures. Dr. Megan Levings is looking for a way to protect the transplanted tissue without compromising other aspects of the normal immune response. She is studying a novel class of white blood cells, known as T regulatory (Tr) cells, which are thought to have the ability to selectively suppress immune responses. Dr. Levings is exploring the molecular and cellular biology of Tr cells to better understand how they develop and act to induce an immune response. Potentially, these cells might be the basis for a more directed approach to controlling rejection.
Research Pillar: Biomedical
Investigation of pathways underlying retinal degeneration
Retinitis pigmentosa (RP) is a form of inherited blindness that results from the death of light-detecting neurons called rod cells. It is usually diagnosed in children, adolescents and young adults and typically begins with night blindness followed by progressive deterioration of peripheral vision (tunnel vision). Dr. Orson Moritz is studying transgenic frogs with the same genetic mutations that cause the condition in humans. His goal is to identify the biochemical pathways that are activated by these mutations and lead to the death of rod cells. To confirm the involvement of these pathways, he is studying transgenic frogs in which these pathways are disrupted to determine whether this prevents development of RP. The research could enable design of therapies to prevent the progression of RP in humans.
Regulation of thyroid hormone-dependent apoptosis and proliferation by the ING tumour suppressor
Thyroid hormones are critical for proper growth and development and are equally important in maintaining good health. Research has shown that these hormones play a key role in regulatory pathways that ensure cells act appropriately when signaled to grow, divide or undergo apoptosis (programmed cell death). Many molecules are involved in these pathways including proteins that are known to contribute to cancer progression. Dr. Caren Helbing is investigating the relationship between ING protein (a growth inhibitor) and thyroid hormones. ING’s tumour-suppressing action is reduced in many cancers, including a subset of breast cancers. Dr. Helbing is exploring how ING may be involved in regulating the way a cell responds to thyroid hormones. Clarifying the relationship between ING and thyroid hormones, may provide new insight into the ways cancer cells bypass normal cellular controls that normally would cause their destruction.
Intrinsic capacity of spinal circuits for restoration of motor coordination after neurotrauma
While the brain is the body’s command centre, connections within the spinal cord control rhythmic activities like walking. The brain contributes to such movements, but spinal cord circuits can coordinate muscle activity on their own, relying on feedback from moving limbs to regulate the pattern. When these connections are lost or altered due to injury to the brain or spinal cord, movement in the arms and legs may be greatly reduced depending on the location and severity of the injury. Dr. Paul Zehr’s research focuses on improving understanding of how coordinated muscle activity in arms and legs can be improved after neurotrauma. He is working with individuals who have had strokes or spinal cord injuries to determine the extent to which enhanced sensory feedback techniques can retrain spinal cord circuits and improve limb coordination. New knowledge gained from this research may lead to more effective methods of improving motor coordination following brain or spinal cord injury.
The contribution of hepatic ABCA1 to HDL levels and composition, and suceptibility to atherosclerosis
Coronary artery disease is a leading cause of death among Canadians. High cholesterol has been identified as a major risk factor for the disease. However, there are two kinds of cholesterol: LDL, the so-called “bad” cholesterol that has been linked to coronary artery disease, and HDL, the so-called “good” cholesterol that has been linked to lower incidence of heart disease. Currently, the medical community’s focus is on decreasing LDL levels, but more than fifty percent of people with premature coronary artery disease have low levels of HDL. A gene called ABCA1 has been identified as critical in the production of HDL, but there is still uncertainty about its function. ABCA1 exists in most tissues of the body, but some tissues – notably the liver – are particularly rich in it. Liam Brunham is investigating the role of ABCA1 in the liver and in the production of HDL. Learning about this gene will increase understanding of how the human body produces and uses cholesterol and how it responds to different diets.
The role of the stem cell antigen, CD34, on mature murine mast cells
In earlier research supported by a MSFHR Masters Trainee Award, Erin Drew disproved theories that CD34, a cell surface protein, was specific to immature blood cells. She found CD34 on immature blood cells, but also on cells lining the blood vessels and on mast cells. Mast cells are known to play a pivotal role in allergic and asthmatic responses. Erin’s work now focuses on CD34’s function in mast cells and how the protein prevents inappropriate adhesion to other cells and tissues. These enquiries will increase new knowledge on how blood cells move around the body and how mast cells can invade tissues and respond to allergens. Ultimately, Erin hopes her work will lead to the identification of targets for the treatment of allergies and asthma.
Factors impeding the success of HIV antiretroviral therapy today: Genetic variation, viral evolution and drug resistance, and cellular reservoirs of HIV
Revolutionary new therapies for HIV/AIDS introduced in the mid-1990s have helped to dramatically reduce deaths resulting from HIV infection. However, despite these advances, the prospect of a cure for HIV infection remains a distant goal. Drawing on the expertise at the BC Centre for Excellence in HIV/AIDS, Zabrina Brumme is researching the genetic factors that may influence HIV disease progression and individual response to therapies, with the goal of better optimizing and tailoring HIV therapy to each patient. Zabrina will also study “viral reservoirs,” cell types that are believed to “hide” HIV for long periods of time over the course of the infection. This project could lead to anti-HIV therapies directed specifically against viral reservoirs, increasing the chance of survival and improving the quality of life for HIV patients.
Functional analysis of the CD34-related molecule, MEP21, in adhesion and stem cell differentiation
Once organisms are fully developed, stem cells are the basis for replenishing cells that wear out or are otherwise destroyed in the normal course of living. Researchers are now looking for ways of identifying and manipulating stem cells to regenerate organs or tissues such as heart muscle, liver, brain or the surface of the lung and digestive tract that have degenerated due to disease. The most well studied stem cells to date, are hematopoietic stem cells, which are produced in the bone marrow and are the precursors from which all blood cells develop. Dr. Kelly McNagny’s laboratory discovered MEP21, a molecule that appears to have a close connection to stem cells since its activation correlates closely with the appearance of stem cells in tissues. This suggests that the molecule may be involved in stem cell production and the processes by which stem cells grow differentially to become a specific type of tissue. Dr. McNagny’s research has shown that MEP21 is required for survival – i.e., mice lacking the molecule die shortly after birth. He is now studying its role in activating adult stem cells, with the goal of finding new ways of purifying and using stem cells to regenerate tissues.
A finite element model of the spinal cord
The way spinal cord tissue responds to different forces is not well understood. Carolyn Greaves is designing a specialized computer model of the spinal cord and its surrounding structures to measure the impact of different types of injury. This type of model of the spinal cord, called a finite element model, has never been developed before. The model will provide detailed measurements of spinal cord response to internal stresses, strains, and pressure changes in spinal fluid, as well as the impact on blood vessels, grey matter (nerve cell bodies) and white matter (nerve fibres). This information will broaden understanding of spinal cord injuries and be used to evaluate potential treatments. As well, neurological changes-such as swelling-occur following a spinal cord injury and can lead to secondary injuries. Carolyn’s model may lead the development of other models that could provide better understanding of these secondary injuries and how to treat them.
The neuromuscular and sensorimotor basis of balance recovery
Falls and related injuries cause loss of independence, reduce quality of life, and increase mortality among elderly people. Fall-related injuries cost Canadians $3.6 billion in 1995. Consequently, reducing the incidence and severity of falls is an important health priority. Dawn Mackey is comparing young and elderly study participants to measure the variables that govern our ability to recover balance following unexpected movements. Maintaining a stable upright posture is essential to daily activities such as walking, turning and rising. However, postural stability declines as we age. Dawn will assess whether balance recovery depends on the strength and speed of muscle response, simultaneous contraction of front and back ankle muscles, where someone’s mental attention is focused, and the intactness and speed of sight and hearing. She hopes the research can be used to design exercise and rehabilitation programs to prevent falls among elderly people.