Type 2 diabetes mellitus is a devastating chronic disease affecting close to two million Canadians. The disease is characterized by a loss of insulin action in tissues such as muscle and a loss of insulin secretion by the islet beta cells of the pancreas. The number of beta cells within the pancreas â an important determinant of the amount of insulin secreted â is decreased in persons with type 2 diabetes. This supports the idea that the progressive loss of insulin secretion in this disease is due to a loss of functional beta cells. The loss of beta cells is associated with the formation of toxic islet amyloid deposits, consisting primarily of the beta cell peptide islet amyloid polypeptide (IAPP or amylin). Although the mechanism underlying islet amyloid formation is not known, impaired processing of the IAPP precursor, proIAPP, has been proposed to be an important initiating event. In type 2 diabetes, elevated glucose and free fatty acids can cause beta cell dysfunction, which raises the question whether elevated cholesterol induces beta cell dysfunction in this disease. Zainisha Vasanjiâs research is aimed at determining whether exposure of beta cells to elevated cholesterol is the trigger for the chain of events that lead to islet amyloid formation in type 2 diabetes. Zainishaâs study may help delineate the cause of the beta cell defect in type 2 diabetes and may lead to new therapies to prevent the progressive loss of insulin secretion in this disease.
Research Pillar: Biomedical
New RNAs Phenotypes from Old by Random Recombination and Selection
The emergence of new viral species or strains by evolution is viewed as a great potential danger to human health. Besides mutation, recombination (shuffling of genes) plays an important role in the evolution of viruses â such as HIV or Hepatitis E. There is significant concern that more dangerous viral strains or species may evolve through recombination. However, the complexity of virus-host systems makes the study of this process very difficult. Using a new method she developed, Qing (Sunny) Wang is using ribozymes (specific functional RNAs) as a model for studying the mechanisms of random recombination in viruses. She hopes that this work will shed more light on how viruses evolve through recombination.
Antibiotic Resistance in Superbugs: Regulation of the Blar beta-lactam sensor of MRSA and the MexAB-OprM multidrug-efflux effector PA3719 from Pseudomonas aeruginosa
Every year, Canada spends hundreds of millions of dollars in the fight against antibiotic-resistant âsuperbugsâ, bacteria that have evolved to outmaneuver the drugs that are designed to kill them. The elaborate resistance machinery that bacteria have developed can be energy consuming for the organism to construct and maintain, so bacteria will activate this defense system only in the presence of antibiotics. This effect is seen within superbugs that are resistant to beta-lactam antibiotics such as penicillin. Mark Wilke is working to understand the regulatory machinery bacteria use to switch on beta-lactam resistance, specifically within the notorious superbugs MRSA (methicillin-resistant Staphylococcus aureus) and Pseudomonas aeruginosa. He is using a technique called X-ray crystallography, which generates atomic resolution âsnapshotsâ of proteins and other molecules in action. His findings could lead to new strategies for combating superbug infections.
Novel redox-elimination mechanism of enzymatic glycoside hydrolysis: A detailed study of Family 4 glycosidases
Carbohydrates are found in every facet of life, not only in metabolic pathways, but also as key mediators in intercellular communication and cellular activity. Associated with these important biomolecules are a class of enzymesâglycosidasesâthat contribute to the breakdown of carbohydrates, allowing for their use as an energy source by the cell. Interruption of these processes can affect cell growth by limiting the supply of available nutrients. With more than 90 different known glycosidase families, the recently-discovered Family 4 glycosidases have been shown to operate through a different mechanism. In addition, this family exists in a number of bacteria, but not in mammals. Continuing in research that was previously funded by MSFHR, Vivian Yip is performing a detailed investigation of the mechanisms of Family 4 glycosidases. Ultimately, she is interested in exploring how inhibition of these glycosidases could be used to develop antibiotics that selectively compromise bacteria, but not the host.
Mining the genome and transcriptome of lung cancer for clinically relevant molecular signatures
Lung cancer is responsible for the greatest number of cancer deaths in Canada. Current chemotherapy treatments are largely palliative, and only a small percentage of patients show a favourable response. Like other cancers, the progression of lung tumours is driven by a series of genetic alterations that can vary significantly between patients. The specific set of changes that occur in any individual tumour influences not only its aggressiveness and outcome, but also the effectiveness of cancer treatment. Scott Zuyderduyn will determine the genetic changes in several hundred lung tumour samples for which treatment and outcome is known. He will then employ computational and statistical approaches to determine which changes can accurately predict how a tumour will respond to different treatments. This research has important implications for determining, at diagnosis, the best choice of cancer-fighting treatment.
Mechanisms of target-dependent neuronal differentiation in Drosophila
Normal nervous system function requires the generation of an enormous diversity of neurons during development. Differences in the identity and function of neurons depend upon differences in the repertoire of genes that the neuron expresses. Differential expression of these genes is controlled by intrinsic factorsâthe complement of transcription factors that exist within the neuronsâ and by extrinsic factors, signals secreted by other cells. Alterations in either of these factors have been implicated in many developmental, psychiatric and degenerative diseases. Dr. Douglas Allan is investigating how these intrinsic and extrinsic signals interact in neurons to selectively turn on the expression of different repertoires of genes in different neurons, so that the neurons attain their appropriate form and function. He is using the fruit fly, Drosophila melanogaster, as a model organism to study these mechanisms, because of the battery of powerful molecular genetic experimental tools available in this organism. Since the basic mechanisms of neuronal development are shared by fruit flies and humans, his work is relevant to understanding how human neurons develop and how disruption of these signals can cause disease.
Examination of the role of cadherin/beta-catenin adhesion complexes in the development and maintenance of synaptic junctions
Synapses of the central nervous systemâjunctions across which a nerve impulse passes from neuron to neuronâare highly-specialized regions of cell-to-cell contact. Deficiencies in synaptic function are central in many psychiatric and neurodegenerative diseases such as schizophrenia, Alzheimerâs, Parkinsonâs and Huntingtonâs disease. Cell adhesion molecules, localized at synapses, are believed to have an important role in the regulation of synapse formation, maintenance and function. Dr. Shernaz Bamji has previously shown that cadherin and beta-catenin adhesion complexes act to recruit and tether synaptic vesicles to presynaptic compartments, and that transient disruptions of these adhesion complexes are important for the sprouting of new synapses. She is now further investigating the cellular and molecular mechanisms by which synaptic cell adhesion molecules regulate the formation, stability, and elimination of CNS synapses. . Understanding the underpinnings of these mechanisms may lead to the identification of new targets for therapeutic intervention in psychiatric and neurodegenerative diseases.
Structural and functional characterization of the vibrio cholerae toxin-coregulated pilus
Vibrio cholerae is a bacteria that infects the human small intestine to cause the potentially fatal diarrheal disease cholera. This disease, which is spread through contaminated drinking water, represents a major health threat in developing countries, with young children being most vulnerable. The toxin co-regulated pili (TCP) on the surface of V. cholerae are important components in the bacteriaâs ability to cause disease in the host. TCP are hairlike filaments that hold the bacteria together in aggregates or microcolonies, protecting them from the host immune response and concentrating the toxin they secrete. The TCP are also the route through which the V. cholerae bacteria is itself infected by a virus called CTX-phi, which enables V. cholerae to produce cholera toxin. Dr. Lisa Craig is determining the molecular structure of the TCP and delineating the regions of this filament that are involved in microcolony formation and in binding to CTX-phi. The information obtained from her studies may lead to vaccines, therapeutics and diagnostics for combating this deadly disease.
Neuromechanical determinants of the metabolic cost of healthy and pathological gait
Walking is a vital means of mobility for most people. While walking is easy for healthy people, for individuals who have suffered a stroke and have partial paralysis of one side of their body (hemiparesis), walking can be difficult. Often, these people will avoid walking, because their gait requires nearly twice the metabolic energy of healthy gait. These increased energy demands may partially explain why stroke patients tend to walk slowly and avoid carrying heavy loads, impairing their daily activities. Dr. Max Donelanâs research aims to advance our understanding of the fundamental principles that underlie locomotion physiology and to apply these principles to directly improve human health. Across the range of his research, he uses a combination of mathematical modeling and empirical experimentation, which involves techniques from biomechanics, energetics and neurophysiology. To study the metabolic cost of gait after stroke, Dr. Donelan is determining the important mechanisms that make normal walking easy and energy-efficient, and how these mechanisms are compromised in individuals with stroke-related paralysis. The results of his research will guide the design of rehabilitation strategies and devices aimed at lowering metabolic cost and increasing patient mobility.
Molecular basis of tenascin elasticity and mechanotransduction
Tenascin is an important family of proteins found in the extracellular matrix of tissuesâthe filamentous structure that is attached to the outer cell surface and provides anchorage, traction, and positional recognition to the cell, and plays important roles in regulating the interactions between cells and the extracellular matrix. It is also known that tenascin mutations are linked to disorders that affect the mechanical properties of skin tissues and joints. However, little is known about the mechanical properties of tenascins and how they are regulated to adapt tissues to withstand force. To study tenascin, Dr. Hongbin Li is stretching single molecules of the protein and examining its mechanical response. He will also evaluate the consequences of disease-causing mutations on the mechanical behaviour of tenascins. These studies will provide new insight into the molecular basis of tenascin mechanics, and help to pinpoint the cause of tenascin-related connective disorders. They may also offer useful information in developing tissue engineering strategies for skeletal repair.