Incidence of coronary artery disease, which involves narrowing or blocking of the arteries and vessels that provide oxygen and nutrients to the heart, has increased two to four times among people with diabetes. Almost 70 to 80 per cent of diabetes patients die from heart failure. Smooth muscle cells form tissue that contracts without voluntary control. These cells significantly contribute to narrowing or blocking of the arteries in diabetes patients. However, the cellular mechanisms underlying the accelerated rate of smooth muscle cell migration in diabetes are not well understood. Dr. Mitra Esfandiarei is investigating these mechanisms and also assessing the role of integrin signaling â cell communication that involves connecting the cell interior to its exterior or one cell to another. Integrin signaling may help regulate the internal framework of cells that affects muscle contraction and smooth muscle cell migration in diabetes. The research could contribute to development of therapies that prevent or delay accumulation of atherosclerotic plaque and blocking of arteries in diabetes type 2 patients. She ultimately aims to reduce the frequency of disease and mortality due to the cardiovascular complications, and improve the health of patients with type 2 diabetes. In 2001, Mitra Esfandiarei was also funded by MSFHR to study how heart muscle cells can survive infection by coxsackievirus B3 during the course of enteroviral myocarditis, an inflammatory heart disease.
Research Location: Child & Family Research Institute
Apolipoproteins and Autoimmunity to Lipid Antigens
The immune system is designed to rid the body of infections and unwanted cells, such as tumor cells or virally infected cells. The decision to target a certain agent for elimination is made by recognizing that a component (antigen) of a bacteria or virally infected cell is «foreign» to the body. Sometimes, however, the immune system can mistakenly target «self» components in healthy tissue, which leads to autoimmune diseases such as multiple sclerosis (MS). White blood cells called T cells are the central players in this decision making and are classically known to target protein components. Recently, however, it has been found that lipid components (ie. fats) can also be targeted by T cells, which is a new paradigm in immune recognition. We have been studying how T cells recognize lipids, and found that a major blood protein, apolipoprotein E (apoE), which was previously known to carry lipids for metabolic purposes, is also playing a role in the immune system to promote the recognition of lipids. ApoE has been known to play a role in many diseases, including MS and atherosclerosis (the disease of blood vessels which leads to heart disease and strokes). These two diseases also share common features in that there is immune system involvement which causes harm, in MS directed against the fatty insulation of nerves (myelin), and in atherosclerosis, immunity against unknown agents, possibly lipids found circulating in the blood. Our findings integrating lipid metabolism by apoE and the immune system thus open up a new area of research of direct relevance to MS and atherosclerosis, and we will set out to demonstrate that lipids are targeted in these diseases, and how apoE is involved to promote this mistaken targeting. Understanding these mechanisms will allow us to better monitor these disease using blood samples from patients, and also point to new strategies to treat disease by dampening or altering the immune response to lipids.
Detection of novel microdeletions and microduplications in persons with intellectual disability using whole genome microarrays
Intellectual disability (ID) is a diagnosis given to persons who have life-long cognitive and adaptive impairments that commence in early life. ID affects about 1-3% of the population, thus nearly 1 million Canadians have an ID. The cause of ID is unknown in at least 40% of all cases. Recent reports have suggested that very tiny chromosome changes are the cause of many cases of ID. These tiny chromosome anomalies are usually not seen using routine microscopic analysis. However, recently developed microarray technology provides an opportunity to detect these very small changes.
Dr. Evica Rajcan-Separovic has used this technology to look for such abnormalities in 200 subjects with ID and have detected very small genetic changes in 16% cases. Some of the genetic abnormalities were seen in more than one individual. Her team plans to extend their array study to 400 more ID individuals in the next 6 years and to examine using molecular methods another 2000 subjects with ID to see if they can find additional individuals with the same abnormalities. By studying a larger number of individuals with the same chromosome change, they will be able to determine what physical features and medical issues are due to that genetic change.
Rajcan-Separovic's next step will be to develop Health Care Watches for each new condition identified. These will describe expected health issues, so that families and physicians can be better prepared to care for individuals with these new genetic syndromes. This approach will eliminate costly multiple testing and searching for answers, and should allow optimal care and health for persons with ID.
Wild-type Huntingtin’s pro-survival function: A potential role in Huntington’s disease pathogenesis and treatment
Huntington's Disease (HD) is an Inherited brain disorder affecting approximately 1 in 10,000 Canadians that causes progressive disability with an inexorable march towards death averaging 18 years after the onset of symptoms. There is currently no cure for HD and no known treatment that affects the age of onset or the progression of symptoms. The underlying genetic defect that causes HD is now known and the mutant HD gene produces an abnormal protein called huntingtin (htt) that damages brain cells. Many research groups around the world are studying how the abnormal htt protein kills cells, but the normal cellular function of htt is not well understood. This proposal is unique in that we will examine the protective role that the normal htt protein may play in the disease process of HD. We previously demonstrated that the normal htt protein has a pro-survival function in the brain and prevents various forms of brain cell death. Our proposed experiments will determine what specific regions of htt are required for this protective role, how protein modifications of htt affect this function, and we will test what effect modulating levels of normal htt have on the progression and development of HD. Based on our preliminary results, I hypothesize that altering the pro-survival function of htt will modulate the process of brain cell injury in HD. Mapping the critical pro-survival regions of htt, investigating the mechanisms by which this function is regulated, and understanding the downstream pathways by which htt modulates brain cell death may provide novel cellular therapeutic targets for HD and for neurodegenerative disorders in general.
Use of the skin immune system and dendritic cells to alter systemic immunity
The skin is the largest organ of the human body and represents the body’s primary interface with the external environment. As such, the skin is challenged by a broad range of factors and conditions. These include both endogenous (genetic, immunologic, and systemic) and exogenous (solar radiation, allergens, irritants, pollutants, and microbes) factors. As a result, the skin is a major site for disease including inflammation and cancer. Dendritic cells are immune cells that begin and coordinate immune responses. The skin is one of the largest repositories of these dendritic cells. Thus, in addition to being a direct target for inflammation, the skin is one of the prime sites where systemic immune responses begin. The proposed program includes four primary themes. The first three themes revolve around the use of the skin immune system (and skin dendritic cells) to modify immune responses (The skin immune system in the induction of immune responses; The skin immune system in the reduction of immune responses and; The skin immune system in disease pathogenesis). The final theme involves the use of pharmaceutical agents to modulate the activity of nonskin derived dendritic cells. The skin offers a unique opportunity to observe and manipulate dendritic cells and thereby the immune system. The focus on the skin as an organ to manipulate immune responses is innovative. This program will lead to a better understanding of the role of the skin immune system in systemic as well as local autoimmune disease (examples include lupus, psoriasis and type 1 diabetes). Further, the program will lead to cost effective strategies to treat and prevent human disease with anticipated improvements in vaccine delivery and efficacy and novel methods to control autoimmune disease.
The MTHFR C677T polymorphism and postpartum mental illness in at-risk women
Psychotic disorders (which include schizophrenia, schizoaffective and bipolar disorders) are common mental illnesses, affecting about 3 per cent of the population. Women face a number of challenges when dealing with these disorders, especially when it comes to pregnancy, childbirth and parenting. Women with a history of a psychotic disorder have substantial risks for a postpartum episode of mental illness like depression or psychosis. Postpartum mental illness carries risks for suicide and infanticide, as well as other less dramatic but still significant problems like difficulties with parenting skills and problems with mother-child bonding and attachment. Research has shown that, in general, psychotic disorders stem from interactions between genetic and environmental influences. The specific genetic variations that increase risk for postpartum episodes of mental illness are largely unknown. Dr. Jehannine Austin will use a new approach to investigate whether a variation to one particular gene contributes to risk for postpartum episodes of mental illness in women with a history of mental illness. This gene is known to encode a protein whose function is dependant on the B vitamin, folate. Dr. Austin will not only look at genetic variations, but will also measure folate levels in pregnant women at high risk of postpartum mental illness. If her work shows that the genetic variation plays a role in risk for postpartum mental illness, it may be possible to decrease risk for postpartum episodes of mental illness by providing folate supplements for these women.
Optimal, evidence-based use of vaccines
Immunization is one of the most powerful tools available in medicine. The number of available vaccines expands each year, reducing infection and disease. Optimal use of these new products can be hampered by gaps in understanding the disease epidemiology, vaccine effectiveness or longevity of protection provided. These gaps also affect decision-making related to resource allocation and prioritization of immunization programs. Dr. Jan Ochnio is working to close these gaps by gathering missing evidence to facilitate vaccine use in several viral and bacterial infections. As a MSFHR Scholar, Ochnio investigated the risk of hepatitis A for children in specific areas of the province. Now, his research is focusing on two areas: investigations of hepatitis A virus infections using population-based assays and saliva/mail-based surveys, and optimizing prevention of meningococcal infections by measuring the levels and duration of protection offered by the various meningococcal immunization schedules in Canada. A better understanding of the most efficient strategies for using vaccines could lead to substantial savings in health care by omitting unnecessary doses and the related costs of providing these doses. Ochnioâs findings will be shared with public health policy experts to be used in finely-tuned vaccination programs and policies that will provide optimal protection for Canadians.
Dietary modulation of mitochondrial function in the prevention of diabetic heart disease
An estimated 150 million people worldwide have diabetes, a metabolic disorder marked by high blood sugar. After anti-diabetic medications were developed, high blood sugar was no longer a primary cause of death for diabetics. Other complications, particularly heart failure, have become a major factor in mortality. Free radicals are unstable and highly reactive atoms. Both type 1 and type 2 diabetes involve increased free radical release in heart cells. Research has suggested that increased accumulation of free radicals irreversibly damages mitochondria, the part of heart cells that helps convert fat into energy for the heart’s pumping action. If the mitochondria are damaged, fat accumulates in the heart. The combination of free radical release, fat accumulation, and lack of energy can kill heart cells, leading to the development of a weak heart in diabetic patients. Dr. Sanjoy Ghosh is studying the benefits of supplementing diet with S-adenosyl methionine and omega-3 polyunsaturated fatty acids. He is researching whether they can lower the release of free radicals, protect mitochondria, decrease fat deposits, and increase energy production in the diabetic heart. His goal: a natural, non-toxic therapy to prevent or delay the onset of diabetic heart disease.
Characterization of retrograde transport machinery and its relationship to amyotrophic lateral sclerosis (ALS) using the yeast model system
Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a rapidly progressive motor neuron disease that causes paralysis and is ultimately fatal. In ALS, motor neurons (nerve cells) are impaired and eventually die. This process breaks the connection between voluntary muscles, which individuals control, and the brain. Other types of brain cells are unaffected, which means patients become paralyzed but their cognitive abilities remain intact. Specialized transport proteins carry survival signals from one end of the neuron to the other. In a mouse model of ALS, the cause of motor neuron disease was found to be due to a mutation in the Vps54 transport protein. In all types of cells, material is transported in a specialized container called a vesicle. In her research, Nicole Quenneville has found that a particular region of the Vps54 transport protein is involved in recognizing the surface of vesicles. Itâs this region that is mutated in the mouse model of ALS, suggesting that faulty recognition and transport of these vesicles may lead to motor neuron disease. Using a yeast model, Quenneville is further investigating whether the Vps54 mutation causes transport defects, and whether the mutation changes the interactions that the Vps54 protein has with other proteins. As well, she aims to identify genes and proteins that work with Vps54 to transport molecules within the cell. Quenneville hopes her research will help identify candidate genes for novel therapies, diagnosis, and assessment of susceptibility to ALS.
Characterizing the role of palmitoylation in the trafficking of multispanning membrane proteins to the cell surface
Molecules are transported to various parts inside the cell to maintain vital functions, such as cell growth and communication. For example, many proteins regulate the intake of nutrients or detect external signals â itâs crucial to cell survival that these proteins are transported to the cell surface so the cells can recognize and respond appropriately to the different stimuli they encounter. However, there is much to be learned about the way these proteins are transported. This is the focus of Karen Lamâs research, in particular, understanding the mechanisms by which the saturated fatty acid palmitate attaches to proteins (I do not work with brain cells, but with yeast cells, which serve as a model) and affects their transport to the cell surface. For example, palmitate attaches to various proteins found in brain cells. Many of these proteins help chemicals called neurotransmitters send signals in the brain, a process thatâs essential for learning and memory. Defects in this communication can result in neurological diseases like Alzheimer, Huntington and Parkinsonâs. Lam wants to determine what causes defective function and transport in these proteins by modeling the processes in yeast cells. Understanding the fundamental mechanisms of palmitate attachment may lead to the development of molecular-based therapies to treat a variety of neurological disorders.