Diabetes mellitus is a chronic disease that affects over 180 million people worldwide. At least two million Canadians currently live with the condition, a figure expected to double in the next 10 years. Type 2 diabetes accounts for 90 percent of cases and has been recognized by the World Health Organization as a global epidemic. Thus, urgent action is needed to reduce the economic and social burden of the disease and its complications. Diabetes is characterized by insufficient production of insulin, a hormone released by the pancreas that regulates blood glucose levels. Type 1 diabetes is an autoimmune disease caused by destruction of insulin-producing beta-cells within the pancreatic islets. Type 2 diabetes is characterized both by resistance to insulin action and by impaired beta-cell insulin production. Inflammation, an immune response to tissue damage, is important in both conditions. Islets from patients with Type 2 diabetes exhibit increased levels of pro-inflammatory cells and proteins. These contribute to beta-cell damage and impaired insulin production, representing a potential target for therapeutic intervention. High circulating levels of glucose and fatty acids, in addition to toxic deposits of a small protein called islet amyloid polypeptide (IAPP), may signal via pattern recognition receptors on cells within the islet to promote an inflammatory state. However, a better understanding of the causes of islet inflammation is required for effective development of targeted therapies. Clara Westwell-Roper’s research focuses on the role of pattern recognition receptor signalling in islet inflammation induced by metabolic stimuli and IAPP. Her research will enhance our knowledge of the mechanisms that contribute to beta-cell death and impaired insulin secretion in patients with Type 2 diabetes. An understanding of the causes of islet inflammation may facilitate the development of new medications that improve pancreatic islet function.
Research Pillar: Biomedical
Congenital Migraine Mutations alter the Calcium-Dependent Regulation of P/Q-type Calcium Channels and Affect Synaptic Plasticity
Migraine headaches affect approximately 15 percent of the Western population. However, the complicated genetic and underlying physiological basis of migraine has resulted in both slow advancement in new treatments and poor understanding of the disease at the cellular level. Familial Hemiplegic Migraine (FHM) is a type of migraine with similar clinical features to typical migraine, and likely with similar cellular mechanisms, but with well-understood genetics. FHM has become a leading model for studying typical migraine. FHM is clinically characterized by migraine headaches, usually preceded by visual or auditory auras (sensations), and accompanied by hemiparesis (one side of the patients body undergoes varying degrees of paralysis during the migraine attacks). The migraine symptoms can last from a few minutes to several days. Approximately 50 percent of patients with FHM have mutations in the CACNA1A gene, which codes for a type of calcium channel protein that is primarily responsible for facilitating communication between neurons in the brain. Paul Adams’ research focuses on identifying FHM genetic mutations in patients and then introducing those mutations into cloned calcium channel genes. The effects of the FHM mutation on calcium channel properties can then be studied by introducing the mutated channel into a human cell line and then studying the channel using electrical recording techniques. Additionally, the effects of FHM mutations on communication between neurons in the living brain will be studied in mice that have been genetically engineered to contain human FHM mutations in their CACNA1A gene. The results of Adams’ research will provide a better understanding of the molecular mechanisms behind FHM, and thereby contribute to the development of more effective therapies for all types of migraine headaches.
The Role of Palmitoylation in the Pathogenesis of Huntington Disease
Huntington disease (HD), is an adult-onset progressive, degenerative disease affecting the neurons of a particular area of the brain called the striatum. The striatum is partially responsible for regulating movement, and HD affects the part of the striatum responsible for inhibiting unwanted movement. The primary symptom of HD is chorea, or involuntary “”dance-like”” movements. Currently, no effective treatment or cures exist, and death occurs on average 15 years after disease onset. HD is caused by a mutation in the Huntington gene where a short sequence at the beginning of the gene is multiplied, resulting in more than 36 repetitions. The mutation is inherited, so that people with HD have a 50 percent chance of passing it onto their children. The mutation has many effects on the function of the Huntington protein (htt), including interfering with how it interacts with other proteins, such as Huntington Interacting Protein 14 (HIP14). HIP14 is a “”PAT”” enzyme, which is a type of enzyme involved in a process called palmitoylation. There is a growing body of evidence to suggest that palmitoylation plays an important role in HD. Shaun Sanders’ research into HD involves the development of a new, genetically modified “conditional knockout” mouse model. Using this model, Sanders can “”turn off”” HIP14 when and where wanted, in a particular organ or area of an organ, like turning a light off in one room but not in another. He will then look for the symptoms of HD in the mouse model. His research will provide more evidence for the role of HIP14 in HD and further validate the model of palmitoylation in HD. The results will also improve our knowledge regarding “”PAT”” enzymes and palmitoylation which will expand the understanding of other neurological diseases, such as Schizophrenia and mental retardation.
Evaluation of Neurogenesis and Synaptic Plasticity in the YAC128 Transgenic Mouse Model of Huntington's Disease
Currently, there are no therapeutic options available to help regenerate lost brain tissue in patients with Huntington’s disease (HD). However, a large body of evidence suggests that the adult brain retains a limited ability to generate new neurons (a process called neurogenesis), and that adult neuronal stem cells that underlie this process may be a possible endogenous source of healthy neurons for the treatment of certain neurodegenerative diseases including HD. Significant strides are being made in understanding how neural stem cells could be used in regenerative transplant therapies in a number of pathologies. However, whether a “”diseased”” brain has the capacity to sustain regenerative therapy remains unclear. Jessica Simpson is studying how HD affects two populations of endogenously active neuronal stem cells. These stem cells normally give rise to new neurons through out life, so they offer an endogenous indicator of how HD is affecting the brains capacity to regenerate. In addition, she will be testing whether non-invasive therapies aimed at restoring adult neurogenesis and synaptic plasticity (i.e. voluntary physical exercise), might be beneficial in reversing some of the cognitive as well as neuropathological and motor deficits seen in HD mouse models. Adult neurogenesis and synaptic plasticity are thought to be involved in cognitive function, namely learning and memory, in the normal adult brain. Her studies will improve our existing knowledge of how adult neurogenesis and synaptic plasticity are affected in the HD brain and thereby improve our knowledge of the pathogenic mechanisms triggered by HD at the neuronal level. Ms. Simpson’s research may lead to the development of restorative therapeutic strategies that recruit endogenous stem cells into degenerated areas of the brain. Such strategies might also be useful for the treatment of other neurodegenerative diseases characterized by the loss of specific neuronal populations such as Parkinson’s disease. Moreover, the results from this study could potentially contribute to the growing body of evidence suggesting that the use of non-invasive therapeutic strategies, such as voluntary physical exercise and environmental enrichment, provide benefit in the treatment of neurodegenerative conditions such as Alzheimer’s disease.
Testing the role of muscle spindles in cortical development and plasticity
A major goal of neuroscience research is to understand the neural changes that underlie adaptations of the motor system and to use this understanding to promote healing after injury. David McVea is studying the role of sensory input in this process from two different perspectives. First, he is testing the idea that muscle spindles, which respond to changes in muscle length, help determine when changes in the motor system are needed and subsequently spur changes in neural circuits. Second, he is studying how spontaneous muscle twitches in very young animals provide sensory feedback that helps to calibrate and organize the brain’s motor circuits. Mr. McVea is using unique optical recording and stimulating techniques to address these topics. Voltage- and calcium-sensitive dyes allow for simultaneous recording of neurons that are active across large regions of the brain. At the same time, lasers can be used to activate any part of the surface of the brain in mice that express the light-sensitive ion channel Channelrhodopsin-2. Because dyes and laser light are applied to the intact surface of the brain, all neural networks and connections are intact, meaning findings are representative of natural functions. This research will provide valuable information about the fundamental ways in which the human brain develops and recovers after injury. Furthermore, the results could inform the development of new treatments that increase or even artificially enhance sensory feedback to maximize the recovery of people who have suffered brain injury.
Light-based mapping of cortical reorganization after stroke in channelrhodopsin-2 mice
Stroke is the leading cause of adult disability. Although the physical damage is irreversible, many deficits seen immediately after a stroke disappear in the following weeks. This spontaneous recovery is partly due a to reorganization of the brain’s circuitry. The adult brain was long thought to be hardwired, but new evidence has demonstrated that the firing patterns of neurons and the connections between them are constantly changing, giving the brain the flexibility to learn, form new memories and adapt to injuries. This plasticity is especially evident after a stroke. Surviving brain areas are not only able to compensate for the absence of neurons lost to stroke, but can even take on functions formerly carried out by the destroyed area. However, whether rewired neurons in reorganized brain regions maintain the ability to perform their original duties has yet to be determined. Enhancement or modification of the brain’s natural repair processes represents a logical target for new stroke treatments, of which there are few. Thomas Harrison’s research will characterise brain plasticity during the period of spontaneous recovery after stroke using a variety of methods, including a new light-based mapping technique. He will track reorganization from the level of brain regions down to single neurons in transgenic mice before and after stroke. The resulting improved understanding of stroke-induced plasticity may enable the identification of the natural mechanisms of recovery that are most beneficial, and provide the opportunity to screen drugs or therapies for their ability to facilitate these biological pathways. In a larger sense, Mr. Harrison’s research will also advance our understanding of plasticity in the adult brain, which has important implications for learning, addiction and recovery from other forms of brain damage.
Function of clathrin-based endocytic proteins during infections by extracellular bacterial pathogens
Most E. coli bacteria live within the intestines of humans and other animals where they help with normal digestion. However, certain types of E. coli cause disease and represent serious global health concerns. For example, diseases mediated by these pathogenic E. coli often lead to gastro-intestinal infections, resulting in severe and persistent watery or bloody diarrhea. These diseases affect a significant population, especially infants, in many developing countries and the associated mortality rates can exceed 30 percent. Previous research by Ann Lin and others has shown that clathrin, a protein that involves endocytosis, plays a key role in generating E. coli-based diarrhea in humans. Expanding on this research, Ms. Lin is now focusing on the identification of clathrin-associated endocytic components necessary for the development of enteropathogenic E. coli infections, using both in vitro and in vivo approaches. Because other bacteria and viruses (such as influenza), also control clathrin-based internalization mechanisms as part of their infection, Ms. Lin’s’s research will not only provide valuable insight into the mechanism of E. coli-based disease, but will also generate new avenues for the development of novel therapeutics to eradicate other infectious diseases.
Borrelidin: a novel therapeutic agent for treatment of inflammatory diseases
Inflammation is the body's normal physiological response to injury, infection or foreign substances. While the ability to mount an inflammatory response is essential for survival, the ability to control inflammation is also necessary for health. Inflammatory diseases such as rheumatoid arthritis, osteoarthritis, Chrohn's disease, ulcerative colitis, inflammatory bowel disease, asthma, allergies, septic shock, atherosclerosis and many others are a group of disorders characterized by uncontrolled or excessive inflammatory responses. Often, clinical intervention is required to prevent tissue damage and organ dysfunction in these disorders. While there have been advances in anti-inflammatory therapies over the years, long term use of steroidal and non-steroidal anti-inflammatory drugs (NSAIDS,) is limited due to drug-induced toxicities such as stomach ulcer, gastric erosion, exacerbation of asthma and nephrotoxicity. Therefore, the identification of novel agents that can effectively suppress inflammatory responses without associated long term toxicities represent a major unmet medical need. One of the key ways that the body controls inflammation is through the expression of immunoregulatory enzymes. An example of this natural immunoregulation occurs in pregnant mammals: cells of the placenta that surround the fetus express an immunoregulatory enzyme called indoleamine 2,3-dioxygenase (IDO). IDO expression protects the fetus from being attacked by the mother's immune system. Earlier research has revealed that the small molecule drug, borrelidin, could be used to specifically mimic the signalling effects induced by IDO expression and suppress the action of inflammatory cells. Nadya Ogloff's research builds on this evidence by providing pre-clinical proof-of-principle data to support further development of borrelidin as a potent immunosuppresive agent for treatment of inflammatory diseases.
The mechanism by which SOCS3 mediates IL-10 inhibition of macrophage activation
Inflammation is a protective response generated by immune cells against infection. However, when inflammation becomes unregulated within the body, it can cause diseases. A key anti-inflammatory regulator of immune cells is a cytokine (a type of hormone), called interleukin-10 (IL-10). The importance of IL-10 in regulating immune cell function is illustrated by the fact that many tumour cells and intracellular pathogens produce or elicit production of IL-10 for their survival. A main target of IL-10 is macrophages. Activation of macrophages by interferons, or bacterial cell products such as lipopolysaccharide (LPS), induces a number of immunologic responses including production of pro-inflammatory mediators such as the cytokine TNF. IL-10 is able to suppress these events by interfering with pathways utilized by LPS, but its mechanism is unclear. Previous research on the intracellular signal transduction pathways utilized by IL-10 has shown that an important component is a protein called SOCS3 which is thought to target specific proteins for degradation. In order to understand how IL-10 uses SOCS3 to inhibit macrophage activation, Tsz Ying Sylvia Cheung’s research is focusing on proteins that interact with SOCS3 in cells stimulated with IL-10. Identification of these proteins will allow for a further research focus on understanding the role they play in macrophage activation and why they are targeted by IL-10. Developing a clear understanding of the mechanism by which IL-10 regulates the network of intracellular signal transduction pathways will better enable the development of therapeutics mimicking the beneficial anti-inflammatory effects of IL-10, and allow for the development of strategies to counter the immunosuppressive effects of certain tumours and immune cell pathogens.
Probing the gastrointestinal microbiota for microbial determinants of asthma
Allergic asthma affects over 100 million people worldwide and more than 20 percent of Canadians. Furthermore, it is increasingly prevalent among people living in industrialized countries. While the underlying cause(s) of asthma remain unknown, there is increasing evidence to suggest that the intestinal microbiota (normal flora) plays an important role in the development of atopic diseases. Data from several large birth cohort studies have indicated that there may be a strong association between alterations in the intestinal microbiota as a result of antibiotic use and increases in the incidence of allergy and asthma in young children. However, the role of the intestinal microbiota in asthma has not yet been explored experimentally, and no attempts have been made to identify microbial species that may be associated with or hinder the development of asthma. Consequently, Shannon Russell is researching how changes in the composition of the intestinal microbiota may induce changes in asthma susceptibility. She is doing a series of experiments designed to determine whether antibiotic treatment during the early stages of life may alter or delay normal immune development and predispose a person to allergic-type diseases like asthma. This research could establish entirely new roles for the intestinal microbiota and may ultimately aid in the development of novel therapies (e.g. probiotics, prebiotics, narrow spectrum antibiotics), to treat or prevent allergic diseases including asthma.