Research Location: University of British Columbia - Point Grey

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality among Canadians, accounting for an estimated 36 per cent of premature deaths. The majority of these CVD-related deaths result from ischemic heart disease (insufficient blood supply to the heart), which is often caused by plaque building up on the inside of blood vessels (atherosclerosis). As tobacco use has declined, elevated low-density lipoprotein (LDL) cholesterol levels have emerged as the major risk factor for the development of atherosclerosis. Treatment of elevated cholesterol has traditionally involved a drug regime of blood cholesterol-reducing statins, coupled with diet and lifestyle changes. However, increasing research evidence is driving health agencies to further lower their recommended target levels for low-density lipoprotein (LDL) cholesterol. These reduced levels may not be achievable with traditional interventions, requiring the development of new combination therapies. Inhibiting the absorption of cholesterol from the gastrointestinal tract is an attractive target for combination therapy with statins. Stephen Lee is investigating a transporter protein that is produced in the intestinal tract during the process of cholesterol absorption and processing. While several preliminary studies have implicated this protein in the cholesterol absorption process, none have investigated how this process is affected by diet. Stephen will examine the role of the protein on the absorption of cholesterol among mice fed one of four specific diets with precise fat and cholesterol contents. The proposed research may lead to the discovery of a new pharmacological target for future therapies that work with statin treatments to reduce cholesterol levels.

Inflammation is a normal biological response initiated by the immune system to help control and contain infections. Inflammatory diseases occur when defects arise in the immune system pathways that co-ordinate either the detection of pathogens, or the subsequent biological response. Single defects in various critical points on these pathways can lead to profoundly abnormal biological outcomes. When defects in critical points in these immune networks are present, two different scenarios with similar outcomes can occur. In some instances, this can result in a response that is insufficient (hypoinflammatory) for clearing foreign microbes from the body, increasing the risk of lethal infections. Alternately, the inflammatory response can be overly robust (hyperinflammatory), leading to chronic inflammation and tissue damage that impairs the immune response. Examples of diseases with hyperinflammatory phenotypes include, cystic fibrosis (CF) and inflammatory bowel disease (IBD). Matthew Mayer is studying the immune systems of children and adults with these diseases. His goal is to identify new proteins in these dysfunctional inflammatory pathways that could serve as potential drug targets. In addition to treating these immune diseases, such drugs could also be used to treat bacterial infections in otherwise healthy individuals by enhancing their immune systems. This research could lead to new therapies for patients who suffer from inherited hyperinflammatory disease. It could also advance the discovery of new, non-antibiotic drugs that could be used to fight off bacterial infections.

Urinary bladder cancer is one of the most commonly diagnosed malignancies in North America. The great majority of cases are superficial carcinomas, where the tumour is confined to the inner layer of the bladder wall. The most common treatment method is known as transurethral resection, which involves the surgical removal of tumour nodules from the bladder wall. However, there is a high rate of tumour recurrence after this surgical procedure. Intravesical chemotherapy, which involves instillation of one or more chemotherapeutic agents into the bladder following resection, has become the treatment of choice for superficial carcinoma. Unfortunately, the major limitation of this treatment is the rapid and almost complete washout of the drugs from the bladder on first void of urine, and low exposure of chemotherapeutic agents to the tumour sites. This can lead to treatment failure. Although drug treatments via bladder instillation following resection have decreased tumour recurrence rates, overall mortality rates for bladder cancer have not changed in Canada over the last several years. New approaches are needed to treat this type of cancer. Clement Mugabe is working to develop formulations of drugs that are not easily flushed out of the bladder. This can be achieved by creating drugs in the form of mucoadhesive nanoparticles –so tiny and sticky. Mucoadhesive nanoparticle formulations have the potential to adhere to the bladder wall, increase drug uptake into bladder tissue and thereby increase the effectiveness of drug treatment. Mugabe’s research will lead to novel formulations, and new information about the factors that influence uptake of drugs into the bladder wall.

Cardiovascular disease remains the number one killer in British Columbia. These diseases include cardiac arrhythmias, which cause the heart to beat too slowly, too quickly, or in an uncoordinated fashion. Arrhythmias arise from dysfunction of the heart’s natural pacemaker: the sinoatrial node. The sinoatrial node consists of a group of cells responsible for generating the electrical impulse that controls normal rhythmic contraction and relaxation of the heart. In order to generate these electrical impulses, these cells possess a group of proteins known as ion channels. These proteins allow ions to selectively cross the cell membrane barrier, generating an electrical impulse that spreads to neighbouring cells. One particularly important family of ion channels are the HCN or ‘pacemaker’ channels which are responsible for generating the spontaneous activity of the sinoatrial node. The assembly and trafficking of these channels to the cell membrane is vital for ensuring our hearts beat in a regular fashion. How the cell accomplishes this task remains an unanswered question. Hamed Nazzarisedeh’s research attempts to uncover the underlying mechanisms that help regulate or contribute to the trafficking of HCN channels in the heart. Specifically, he is examining the role in which N-linked glycosylation of these proteins may factor in this regulation. His research will contribute to further our knowledge about how various forms of cardiovascular disease associated with HCN channel disruption arise in the heart. Ultimately, this work could aid in the discovery of novel treatment strategies.

The molecule interleukin-7 (IL-7) is an important regulator of the development and signalling function of T cells, the white blood cells involved in fighting off infection and coordinating an efficient immune response. Loss of IL-7 signalling in humans results in a complete lack of T cells, demonstrating the necessity of IL-7 in the development of these important cells. After T cells mature, they circulate through the blood, searching out invading pathogens, mounting an immune response and clearing the infection. This process generates specialized memory T cells, which are able to mount a stronger and more efficient immune response upon subsequent encounters with the same pathogen. Memory cell development is the basis of vaccination, which serves to “prime” the immune system to ward off infections. Growing evidence indicates that not only is IL-7 essential in the development of these memory T cells, but that its overproduction is also implicated in a number of immune system cancers. Lisa Osborne was previously funded by MSFHR for her early PhD research training. She is now continuing her studies of IL-7. Using a number of genetic models of IL-7 signalling, Osborne will clarify the IL-7 mediated biochemical pathways that are involved in a number of T cell processes. She aims to demonstrate which molecule or pathway is primarily involved in the de-regulated growth of T cells that leads to cancer. Ultimately, this research could guide the development of vaccines that rely on the generation of memory T cells against a particular pathogen. Her work will also provide insights into the development of immune system cancers, and potentially a novel treatment approach.

White matter is the part of the nervous system composed mainly of nerve fibres covered by a lipid-dense sheath of myelin. Myelin is produced by cells known as oligodendrocytes, and is responsible for increasing the speed of electrical impulses throughout the nervous system. White matter disorders, such as multiple sclerosis (MS) and spinal cord injury (SCI), comprise a devastating group of conditions that affect millions of people around the world. Although these disorders may have different features, they are all characterized by myelin damage that will not sufficiently repair (remyelinate). While the exact cause of this insufficient remyelination is unknown, one thing is clear: for myelin repair to occur, oligodendrocyte precursor cells (OPCs) need to proliferate and migrate to areas of demyelination, to differentiate, and to then remyelinate denuded neurons. While the transplantation of cells with the potential to myelinate is feasible, there are significant barriers for effectively translating this technology into clinical treatment. An alternative strategy is to activate precursor cells within the host tissue (endogenous cells) to mobilize and promote repair. Jason Plemel was previously funded by MSFHR for his work studying oligodendrocyte transplantation following spinal cord injury. He is now exploring the dynamics of cell-based repair via endogenous cells. He is studying the capacity of oligodendrocytes to self-renew and replicate under normal and disease conditions. He is also investigating possible inhibitory signals at the region of damage that could inhibit endogenous repair, and whether these signals could be blocked to promote remyelination. Plemel anticipates that this work could ultimately lead to new targets for drugs that promote regeneration of myelin in a number of white matter disorders.

Myocarditis is a disease that results in inflammation of heart muscle. Myocarditis and dilated cardiomyopathy (DCM), a condition in which the heart becomes weakened and enlarged, are believed to be continuing stages of an autoimmune disease of the heart. This condition can progress to a stage that requires heart transplantation. Myocarditis is often brought on by a viral infection. In humans, coxsackie B viruses (CBV) are the most frequent cause of viral-induced myocarditis. It is estimated that 30 per cent of new DCM cases in North America are the result of CBV infection. Maya Poffenberger’s research aims to determine the specific immune components that control myocarditis disease severity following viral infection. She is studying cells and molecules that control immune cells. Using mouse models that lack certain immune genes, Poffenberger will be able to identify the genes that influence the induction and severity of myocarditis from CBV infection. With knowledge of how myocarditis is induced and controlled, researchers will be able to develop better disease specific therapies that target immune genes important to disease induction and severity.

The ABO blood groups – comprising the A, B, AB and O blood types – are vitally important in blood transfusion and organ transplantation. The four types are differentiated by the presence or absence of two sugar antigens on the surface of red blood cells: a terminal alpha-1,3-linked N-acetylgalactosamine (A-antigen) or an alpha-1,3-linked galactose (B-antigen), both of which are absent in the O-blood type. As all individuals have antibodies to the antigen(s) they lack, transfusion with an incorrect blood type results in destruction of the incompatible blood cells, which can result in death. The enzyme EABase is capable of releasing both the A and B trisaccharides from the surface of red blood cells, giving it the potential to be used to convert blood cell types by the addition or removal of their antigens. Fathima Shaikh’s studies seek to determine the mechanisms underlying EABase activity, and identify the residues that are created as a result. Knowledge of these enzyme properties is crucial for the next stage of the project: engineering EABase into a glycosynthase, which is a mutant form of the enzyme that can synthesize (form) antigens, rather than removing them. She will conduct further work to optimize the efficiency of this glycosynthase, as well as increasing its synthetic utility by broadening its ability to transfer different sugars. If Shaikh’s experiments are successful, this process would allow for the conversion between blood groups. These enzymes could be of great benefit to human health, helping to overcome shortages in donated blood, and helping in the modification of related antigens on other cell types.

Antibodies are proteins produced by the immune system. They work by selectively and tightly attaching themselves to infectious bacteria, viruses, and other pathogens, neutralizing their disease-causing abilities. The natural role of antibodies in clearing infections has prompted the pharmaceutical industry to invest billions of dollars in attempts to produce new antibody therapies to treat rheumatoid arthritis, cancer, cardiovascular disease, HIV/AIDS, and other diseases. As a result, antibodies have become the most rapidly growing class of therapeutic drugs over the last decade. One successful example of an antibody-based therapy is the drug Herceptin, which treats a highly-aggressive form of breast cancer. In order to produce vast quantities of antibodies required for research and therapeutic use, antibody-producing cells are currently fused to immortal cancer cells to allow them to be grown in laboratory culture. Successfully creating antibody-producing fused cells can involve hundreds to thousands of attempts, requiring many years and millions of dollars in research money. MSFHR previously funded Anupam Singhal as he used micron-sized fluid-handling devices and nanotechnology to allow the study of stem cells at the single cell level. He is now using these approaches to rapidly and inexpensively produce antibodies. He is working on a novel technology that is sensitive enough to detect antibodies produced by single cells, and determine which ones are producing the optimal antibody. Then, the genes responsible for antibody production in these cells can be isolated, cloned and inserted into cell lines for production. As a demonstration of this technology, human antibodies against the influenza virus will be developed. This technology could have far-reaching impacts on the rapid and inexpensive development of breakthrough therapeutic drugs and diagnostic agents.

Inflammation is the response of the body to infection or injury, triggered by the release of proteins that initiate inflammation. Amongst these proteins are members of the chemokine family. Chemokines act as biological beacons, guiding the migration of white blood cells (WBC) from blood vessels to the affected tissue. The structure of chemokines is important to their function. One end of the chemokine binds to tissue and vessels to create a path for white blood cells to follow; the other end interacts with a receptor on the surface of the WBC, prompting the release of further inflammatory mediators that spread the inflammatory response. Recruited and activated WBC attempt to isolate and destroy infectious agents and to prevent further damage. WBC – and in particular cells called macrophages – then help resolve the inflammatory response. In chronic inflammation, continual recruitment and activation of macrophages results in excessive production of reactive molecules that cause host tissue damage, as observed in diseases such as rheumatoid arthritis, multiple sclerosis and chronic obstructive pulmonary disease. The apparent deregulation of macrophage movement may be a result of a change in the structure and function of chemokines. Matrix metalloproteinases (MMPs) are a family of enzymes that modulate chemokine activity by cutting off a portion of either end of the chemokine, which keeps it from functioning properly. Amanda Starr is looking at the functional effects of MMP cleavage on chemokines that recruit and activate macrophages, determining whether cut chemokines are more able to attract and activate macrophage-like cells. She is also developing a technique for detection and quantification of both full-length and cut forms of chemokines from tissue samples. Ultimately, this knowledge could lead to more appropriate and directed therapeutics for the treatment of chronic inflammatory diseases.