Research Pillar: Biomedical

Type 2 diabetes, or diabetes mellitus, is a growing epidemic and a major health problem worldwide. In Canada, the prevalence of diabetes in the general population is around five per cent, but rates as high as 40 per cent have been reported for some indigenous groups. Diabetes can cause serious health problems, including kidney failure, heart disease, stroke and blindness – costing Canada’s health system more than $13 billion annually. It is known that diabetes results from a progressive loss of functional insulin-releasing pancreatic beta-cells. Research evidence suggests that reduced beta-cell survival may be a critical event in this process. The mechanisms underlying beta-cell death in diabetes remain unresolved, but it is becoming increasingly evident that intracellular calcium signals play a vital role in most known types of cell death. Dr. Dan Luciani is examining the role of the ryanodine receptor (RyR), a calcium handling protein, in the death of pancreatic beta-cells. His recent work with colleagues has demonstrated that the flux through these calcium channels regulates beta-cell survival in culture. Using mouse models, he now intends to determine if defects in RyR signaling may predispose to diabetes by testing what happens to beta-cells’ ability to control blood sugar levels when RyR is missing. These studies will lead to a better understanding of the molecular mechanisms that regulate the function and available mass of insulin secreting beta-cells. Ultimately, this knowledge may lead to novel strategies for the treatment, and eventually cure, of this increasingly prevalent disease.

The genetic basis of many facial defects remains unclear. One of the reasons is that we only have a partial picture of gene expression during facial development – when, and in what sequence, particular genes are turned on and off to give rise to the bones, nerves and muscles of the face. This enables the same tissues, which are used in all parts of the face, to arrange themselves in particular patterns to create to a fully-formed face. Dr. Suresh Nimmagadda focuses on how the lower and upper jaws are formed during embryonic development, arising from tiny buds of tissue surrounding the mouth. In particular, he is studying retinoic acid (RA) and bone morphogenetic proteins (BMP), which are secreted during development. He hopes to reveal the roles played by gene targets of BMP and RA in establishing jaw identity. The long term goal of his research is to improve our understanding of the normal and abnormal facial development, forming the basis for new ways to prevent facial defects.

Pathogenic E. coli bacteria cause severe intestinal infection and diarrhea in humans, leading to millions of cases of infection every year. The virulence of pathogenic E. coli and many other gram-negative bacterial pathogens (a bacteria type characterized by its membrane structure) is determined by the type III secretion systems (TTSS). TTSS are multi-protein macromolecular “machines” that mediate the secretion and translocation of bacterial proteins into the cytoplasm of eukaryotic cells – a key step in causing infection. Most of the 20 unique structural components constituting this secretion system are highly conserved among animal and plant pathogens and are also evolutionarily related to proteins in the flagellar-specific export system, another protein secretion system that has been extensively studied. However, real hard biochemical analysis of TTSS has not been done. Dr. Hendrikje Oldehinkel is investigating how the TTSS is built and how it works. She is dissecting protein to protein interactions and assembly of the type III secretion apparatus in enteropathogenic E.coli and in a mouse pathogen, Citrobacter rodentium. Her work employs a combination of biochemical techniques: electroforesis, immunoblotting, stable isotope labelling, mass spectrometry and electron microscopy. Oldehinkel’s research will contribute to the understanding of the structure of TTSS and the role the components of the type III secretion system play in the architecture and function of the system. Understanding TTSS is important for finding new therapeutic options against not only gram-negative bacterial pathogens, but also against many other disease-causing pathogens.

The ability of an organism to perceive its environment and to respond accordingly is a key survival factor for any species. An important example of environmental sensing is the evolution of antibiotic resistance among bacteria, which is a significant challenge for fighting and containing infections in hospital and community settings. These adaptations by disease-causing bacteria allow them to sense the presence of drugs and respond by producing agents to resist the antibiotic. Multidrug resistant bacterial strains have emerged and are increasing in frequency, making treatment more costly and such infections more lethal. Dr. Gerd Prehna is studying the structures and pathways within bacteria that enable this to happen. He is studying in salmonella a novel antivirulence pathway that regulates bacterial populations within the host. Disruption of this process would lead to an unorganized effort by a bacterial infection to maintain itself within a host, reducing its ability to cause illness. He is also studying methicillin resistant staphylococcus aureus, or MRSA, which has evolved a complex sensor molecule that binds to antibiotics and then relays a signal for the bacteria to express resistance factors. By solving the complete three-dimensional structure of this antibiotic sensor, he hopes to determine the mechanism by which this signal is relayed. By learning more about how disease-causing bacteria detect antibiotics, communicate with each other, and collectively mount a defense against these drugs, Prehna hopes this knowledge might be exploited to block sensory and communication pathways, making the bacteria once more susceptible to antibiotics.

The outer surfaces of mammalian cells are covered with a dense and complex array of sugar molecules. These sugars are important in many essential biological processes such as cell recognition, communication, neuron growth and immune defence. However, they are also used as attachment sites by a diverse range of disease-causing microbes and their toxins, and have been implicated in tumour cell metastasis. Many of these sugar-containing structures contain an essential sugar, sialic acid. The enzymes that transfer sialic acid onto these sugar structures are known as sialyltransferases. These enzymes are able to recognize numerous different types of sugar configurations. In fact, the human genome encodes at least 20 distinct sialyltransferases. Despite the importance of these enzymes, researchers know little about their molecular structure, their mechanisms, how they recognize their targets or how they are regulated. Dr. Francesco Rao is investigating the structure and mechanism of a mammalian sialyltransferase. This will give, for the first time, insight into how such enzymes work at the molecular level. This information could also be used to determine ways these enzymes could be therapeutically inhibited to combat infection or cancer metastasis.

Biopharmaceuticals are molecules produced using biotechnology, rather than chemistry, for therapeutic purposes. Biotechnology uses microorganisms (such as bacteria or yeasts) or biological substances (such as enzymes) to manufacture pharmaceutical compounds. Many biopharmaceuticals are very large proteins, which show considerable promise in the treatment of a wide range of diseases. Unfortunately, owing to the complex mechanisms that the body requires to regulate its own proteins in the bloodstream, foreign proteins in the form of medicines are typically rapidly destroyed or removed from the circulation by the body. Sugars found on the surface of mammalian proteins protect provide protection from destruction by circulating protein-degrading enzymes. They also provide a signal when it is time for a protein to be removed from the blood. Dr. Jamie Rich is investigating whether adding specific sugars to protein drugs could help them last longer in the bloodstream and be more effective. He is working to develop an enzyme that can “build” a particular type of sulphur-containing sugar onto the surface of the protein drug. This promises to protect the protein from degradation, prevent the exposure of sugar-based clearance signals, and allow the protein to function normally as an effective long-lasting drug. Creating longer-lasting drugs would reduce the required amount and frequency of dosages, resulting in reduced drug costs. If successful, this approach could be applied to a wide range of proteins that are currently used as drugs or are in the drug development stage.

Tendon has to withstand high tensile forces to do its job properly, acting as a mechanical link between muscle and bone to allow joint movement. Repetitive-use tendon injury, known as tendinopathy, affects workers in many key Canadian industries, as well as professional and recreational athletes. Standard anti-inflammatory treatments are unsuccessful in treating tendinopathy, and new treatments are needed to relieve the burden of chronic tendon pain. Normal tendon is composed of rope-like molecules (type I collagen). In contrast, in tendinopathy the collagen can become spongey – like in cartilage (type II collagen). The tendon becomes less able to resist tensile forces, and more prone to microtearing, pain and rupture. Dr. Alexander Scott is investigating what triggers tendon cells to switch their metabolism to produce less type I collagen and more type II collagen. Scott is conducting a combination of molecular and biomechanical studies both with tendon fibroblasts and with tendon progenitor cells. Scott is also studying transcriptional regulation during tendon injury using a transgenic reporter system, and in patients with tendinopathy. Scott’s research is aimed at developing evidence-based treatments for chronically painful tendons. Ultimately, this could open up new therapeutic options for restoring tendon health.