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.
Research Pillar: Biomedical
Characterization of the molecular phenotype of T regulatory cells
One of the major problems with organ transplantation is preventing the recipient’s immune system from rejecting the new organ. Currently, patients must follow a strict regime of immunosuppressive drugs for their entire life, which can seriously compromise their immune system and place them at significant risk. The development of a method to induce long-term drug-free acceptance of transplanted tissue and/or organs would have tremendous implications for both patients and the health care system. Research on a newly discovered class of cells called T regulatory cells (Tregs) is focused on finding a better solution to the problem of organ rejection. While researchers know that Tregs are capable of suppressing the activity of other T cells and that they play a significant role in regulating immune response, they do not have a clear understanding of the molecular mechanisms which trigger these actions. Natasha Crellin is studying the characteristics and molecular markers unique to Tregs, aiming to provide further understanding of the differentiation and function of these cells. The goal of her research is to better understand the potential for manipulating the body’s own immune response to replace use of immunosuppressive drugs in preventing organ rejection following transplantation.
Overcoming the barriers to axonal regeneration at the dorsal root entry zone in the acute and chronic setting
Traumatic injuries to the nervous system, such as spinal cord injury, can exert enormous physical, psychological, emotional and financial costs to the individual, their families and to society. A major physical consequence of spinal cord injury is sensory dysfunction (loss of normal sensory functions, including touch, pain, and temperature, and an inability to perform accurate motor tasks). All too often, this loss of sensory function is permanent, as spinal sensory nerves fail to regenerate after injury. There are many molecules within the nervous system that are capable of inhibiting the regeneration of nerve fibres. However, the exact mechanisms responsible for halting regrowth of sensory nerve fibres into the spinal cord after injury remain undefined. Dr. Lowell McPhail’s research objective is to identify and overcome the barriers to sensory fibre regeneration, following both acute and chronic dorsal root injury. Specifically, Dr. McPhail is examining injuries at the dorsal root entry zone (the point at which sensory axons enter the spinal cord), as it serves as an excellent system to model the environment of regenerating axons bridging the spinal cord injury site. Dr. McPhail is also investigating the mechanisms responsible for the ability of spared or uninjured sensory neurons to partially compensate for the lost sensory input following dorsal root injury. His research will attempt to identify potential therapeutic strategies for neurotrauma including, sensory nerve injuries, spinal cord injury and brain injuries.
Substrate spectrum of matrix metalloprotease-2 in physiology and pathology
Matrix metalloproteases (MMPs) are a family of extracellular proteases (enzymes) which reside outside cells and initiate the breakdown of proteins that mediate cellular signals. Processing by MMPs can activate, deactivate, or functionally convert signaling proteins. Within the MMP family, MMP-2 plays a pivotal role in cancer spread, since collagen IV degradation by MMP-2 allows tumor cells to penetrate the surrounding tissue. While MMP-2 is an attractive drug target for cancer treatment, clinical trials have shown that drugs which interfere with this enzyme cause severe side effects, partly because the protease is believed to play a part in so many other cell functions. Dr. Oliver Schilling is using innovative proteomic tools to identify and characterize novel MMP-2 substrates on a system-wide scale. His project aims to identify the abundant variety of natural substrates of MMP-2 as well as to the roles of MMP-2 and the cellular signaling pathways that the protease regulates. Given the prominent role of MMP-2 in tumor development, this knowledge has the potential to assist in the development of cancer drugs which are more effective and have fewer side effects.
Novel strategies for genetic modification and expansion of hematopoietic stem cells
Throughout life, blood cell production is dependent on a rare cell found in the bone marrow called the hematopoietic stem cell. This cell has the unique ability to divide and make identical copies of itself and also to generate progeny cells that can expand and acquire the specialized properties of mature circulating blood cells. Stem cells underpin a wide range of transplantation-based therapies for cancer, leukemia and genetic disorders. The use of these cells for therapeutic purposes requires genetic manipulation of hematopoietic stem cells, which involves inserting gene products directly into the cell’s genome. This procedure can also negatively affect chromosomes flanking the insertion site, causing variations in normal gene expression and malignant growth. Dr. Eric Yung is addressing these issues by developing methods to introduce new genes into stem cells without inserting them directly into the host genome. His strategy is to adapt and modify the ability of certain viruses to insert genetic material into cells. These methods may provide safer and more robust ways to achieve high level expression of genes. They may also aid understanding of the function of specific genes (for example genes that cause cancer) and the development of new methods to expand stem cells and develop new therapies for genetic disorders.
Developing a Chlamydia trachomatis vaccine by optimizing dendritic cell responses
Chlamydia trachomatis is the most commonly reported sexually transmitted infection (STI) in Canada. In BC alone, there were 7000 cases reported in 2003. Although antibiotic treatment is effective, more than half of all infections escape detection and timely treatment because they are asymptomatic in the early stages. Left untreated, the infection can lead to chronic pain and infertility. The development of an effective vaccine to prevent C. trachomatis infection is an urgent public health priority. No vaccine has been developed for C. trachomatis since an inactivated whole cell vaccine failed in trials in the 1960s. In order to better understand how the immune system responds to the bacteria and to develop candidate vaccine preparations, Dr. Michelle Zaharik is using cutting edge immunological and gene array technologies to probe how the immune system responds to C. trachomatis. She is looking particularly at dendritic cells (DCs) which play a role in activating the immune system to mount a defence against invading pathogens and are the subject of intense interest for vaccine development. Michelle’s study will identify the specific DC responses necessary to develop protective immunity against C. trachomatis. Ultimately, this may contribute to the development of vaccines specifically targeted to preventing chlamydial infections.
Structural and biochemical analysis of the essential type III secretion system ATPase from Gram-negative pathogenic bacteria
Infection by gram-negative bacteria is a growing threat to humans, animals and plants. The severity of disease and death rate associated with these infections continues to grow because of the increase in antibiotic-resistant strains of these bacteria, including strains of Yersinia, Shigella, Salmonella, Pseudomonas, Chlamydia and enteropathogenic Escherichia coli (EPEC). In several of these organisms, disease-causing properties are dependent upon a type III secretion system (T3SS). The T3SS is a complex of more than 20 unique protein components structured into a syringe-like apparatus, which delivers the virulence factors (toxins) from the bacteria directly into the host cells. A key component for toxin insertion is the activity of a type III ATPase, an enzyme that provides the energy for this process and acts as a gatekeeper on the bacterial inner membrane. Dr. Raz Zarivach’s goal is to determine the first three-dimensional molecular structure of this type III ATPase and further understand its mechanisms and role in virulence. He hopes his work will lead to the design of new drugs that will inhibit this secretion system and protect against these common disease-causing bacteria.
The role of specific genomic alterations in the aggressive nature of small cell lung cancer
Lung cancer remains the leading cause of cancer death for both men and women in Canada and Small Cell Lung Cancer (SCLC) accounts for about 25% of all cases annually. Patients diagnosed with SCLC have a very poor prognosis, with statistics indicating that only 10% of patients will survive past 5 years. This survival rate has seen little improvement over the past several decades and new targets for therapy and diagnosis of SCLC are desperately needed. SCLC is particularly challenging for researchers because samples are relatively difficult to obtain. Because the type of cell from which SCLC develops is not known, it is also difficult to define normal gene expression (RNA) levels for comparison. Bradley Coe is investigating SCLC gene expression levels by focussing on changes found in the DNA rather than in the RNA. Analysis of DNA has a significant advantage in that the source cell is not needed for establishing a baseline. Bradley is comparing the DNA profiles of SCLC cells with profiles generated from similar types of lung cancer which are less aggressive – an approach that has been made possible because of new genome comparison technology. The results of his research will include a list of genes which may contribute to the aggressiveness of SCLC. His research will also contribute to increased knowledge of the biology of SCLC, which will assist in the classification and diagnosis of this disease and in the identification of potential new targets for drug therapy.
P21-activated kinases role in epithelial morphogenesis and cytoskeletal polarity
Cell shape and cell movement play vital roles in organ formation and the sculpting of body shape in the development of multicellular organisms. The Rho family of small GTPases are key regulators of cell shape and cell movement through their participation in signaling pathways involved in a variety of cell processes. These proteins function as “molecular switches”, with the ability to alternate between active and inactive states. Malfunction of these switching mechanisms has been implicated in a variety of disorders including cancer, and a number of inherited conditions such as X-linked mental retardation and faciogenital dysplasia (Aarskog syndrome). These proteins have also been shown to be key regulators in wound healing. The p21-activated kinases (Paks) are proteins that have been shown to alter activity of the Rho GTPases Cdc42 and Rac, and are linked to the regulation of the actin cytoskeleton. Previous studies have demonstrated Pak’s function in the establishment of cell shape and movement via regulation of the actin cytoskeleton. However, the exact nature of Pak within the signaling cascade remains unclear. Ryan Conder’s recent studies have suggested a role for Pak in either the establishment or maintenance of specific membrane surfaces of a cell that are required for tumor suppressor proteins to position themselves properly. Using Drosophila (fruit fly) developmental processes as a model system, Ryan is studying the proteins involved in these signaling networks and establishing the mechanisms by which these developmental processes are regulated. He hopes that what he learns about these signaling pathways in Drosophila will shed light on their roles in human development and disease.
Role of the Ubiquitin/ Proteasome pathway in Coxsackievirus-Induced Myocarditis
Myocarditis is an inflammatory heart disease caused by the coxsackievirus that enlarges and damages the heart and may lead to sudden heart failure. In severe cases, heart transplant is the only treatment for this condition. When the infection occurs in newborns and children the outcome is frequently fatal. Even with non-lethal infections, long term heart failure is a common result. Research has shown that inhibiting the major intracellular pathway for protein degradation, called the ubiquitin/proteasome pathway, limits the ability of the virus to multiply and infect other cells. The proteasome are immune cells that accumulate and destroy unwanted or damaged proteins. The ubiquitin is a molecule that latches onto damaged or mutated proteins and flags them for destruction by the proteasome. By blocking this pathway, research has shown that the coxsackievirus can be prevented from producing proteins, which may affect the ability of the virus to replicate. Guang Gao is studying the importance of the ubiquitin/proteasome pathway in coxsackievirus replication and in virus-induced acute heart injury and chronic heart failure. His studies will provide important insights into the interaction between the virus and the ubiquitin/proteasome system and ultimately may lead to the development of more effective methods of preventing or treating myocarditis.