While most people understand paralysis due to spinal cord injuries, they are less aware of the other consequences of these injuries. Damage to the spinal cord can also result in chronic pain, loss of sexual function, and loss of control of bodily functions, including control of the bladder and bowels. Loss of bladder control is particularly problematic because it frequently results in bladder infections requiring medication, and sometimes hospitalization. Because most spinal cord injuries (SCIs) do not involve a complete disconnection of the brain from the spinal cord, there is potential to make new connections in the spinal cord by stimulating neurons that survive the injury. Leanne Ramer is researching the potential for growth of uninjured neurons in the spinal cord to improve bladder function after SCI. She will examine bladder function in rats with SCI, with and without treatments to enhance growth of neurons in the spinal cord. The outcome of these studies may provide new avenues for exploring ways of improving bladder control and quality of life following spinal cord injury.
Research Pillar: Biomedical
Spinal cord regeneration following cellular transplantation: actions and mechanisms of olfactory ensheathing glia
Spinal cord injury results in devastating, permanent consequences for the injured individual when the nerve cells that form the spinal cord and connect the brain to the muscles of the body fail to regenerate. One of the most promising therapies for nerve cell regeneration is transplantation of olfactory ensheathing cells, which are involved in our ability to smell and help nerve cells in the olfactory system to continually regenerate. Research has focused on the transplantation potential of olfactory ensheathing cells, which form a protective layer around nerve cells and also play a role in regulating their function. Restoration of some motor functions has been reported following transplantation of these cells, but the mechanisms by which this occurs is not understood. Further, only some spinal cord injuries respond to this treatment and the reason for that is also unknown. Miranda Richter is studying nerve cell growth in vivo and in vitro to determine the intrinsic differences between different tracts of the spinal cord in their responsiveness to ensheathing cells. This will enable her to understand what mechanisms are used by ensheathing cells to promote nerve cell growth. By dissecting the mechanisms of this action, her research may contribute to the development of a more effective treatment for spinal cord injury.
Characterization of novel isoforms of tapasin and their function in immune modulation
A healthy immune system constantly monitors the body, helping to detect and eliminate infected cells and those that become cancerous. This system is mediated by a group of molecules called MHC Class 1, which adhere to and present a sample of the contents of a cell for scanning by T cells. T cells are specialized immune cells that are programmed to recognize and destroy abnormal or infected cells. In auto immune disease, such as Crohn’s disease, Lupus and Rheumatoid arthritis, this system breaks down and the T cells kill both abnormal cells as well as healthy ones. Robyn Seipp is researching the role of a specific molecule within the MHC Class 1 assembly pathway called tapasin. This molecule assists in the assembly and determination of which proteins are presented to the T cells on the cell surface. Her research is examining two newly discovered variants of the tapasin molecule that appear to function differently. She is studying these variants of tapasin to determine their effect on how, when and where immune responses to various pathogens or tumours are made. Results from her research will help better understand how tapasin contributes to the body’s ability to mount immune responses to pathogens and cancers while avoiding autoimmune diseases. A better understanding of their function could have important implications for vaccine design and may lead to better application of generalized tumour therapy.
The search for novel regulatory elements in C.elegans
Gene expression is the process by which a gene’s information is interpreted via RNA messengers to regulate all aspects of cell growth and function. Errors in this complex process can cause birth defects and diseases such as cancer. Although the mapping of the human genome was a major breakthrough in gene research, much remains to be learned about the molecular mechanisms which determine when a gene will be turned on and off (i.e. signaled to start or stop the production of messengers to co-ordinate specific types of cellular activity). Monica Sleumer is studying how genes are controlled at the molecular level. She is using the nematode (roundworm) C. elegans as a model organism because its genome has been fully sequenced (its genes are known) and it has been shown to share basic regulatory elements with humans. Using sophisticated bioinformatic methods for sorting and analyzing genetic data, Monica is investigating what turns genes on and off under different conditions and in different tissues. Ultimately, results from Monica’s research on the C. elegans will lead to new understanding of the much more complex human genome and the consequences for health when regulation errors occur.
Engineering of islets to produce the anti-diabetic hormone GLP-1
More than 2 million Canadians and 135 million people worldwide have diabetes, a chronic medical condition characterized by a lack of insulin (Type 1), or insensitivity to insulin (Type 2), a blood sugar-lowering hormone. Type 1 diabetes can be treated by transplantation of islets, which contain the insulin-producing cells, to patients, but use of this therapy is limited by the huge volume of islets required to treat all Type 1 diabetes patients. As a result, most continue to rely on insulin injections to help control blood glucose levels. Glucagon-like peptide-1 (GLP-1) is produced in the intestine and has numerous anti-diabetic effects. Clinical trials are currently investigating GLP-1 as a treatment for Type 2 diabetes. Other recent studies show GLP-1 also enhances the growth of islet tissue. As a 2003 MSFHR Trainee, Rhonda Wideman investigated the effects of GLP-1 on the growth and survival of transplanted islets to determine if GLP-1 reduces the amount of islets needed to treat Type 1 diabetes in transplant recipients. Now in a PhD program, Rhonda is examining the therapeutic potential of engineering islets to produce GLP-1. She is investigating whether islets in which GLP-1 production has been induced will indeed survive and function better following transplantation. This would reduce the amount of islets necessary for a successful transplant and enhance post-transplant islet function. Ultimately, Rhonda hopes her studies will contribute to improved islet transplantation protocols, which are more effective and less reliant on limited supplies of donor islet tissue.
Molecular characterization of a phosducin-like protein and its co-operation with the protein folding machine CCT
Each year millions of people worldwide are diagnosed with diseases related to disordered protein folding. Normally, protein chains fold into a defined shape in order to function properly and when this process is disrupted, diseases such as Huntington’s, Alzheimer’s, cystic fibrosis and some forms of diabetes occur. The regulators of protein folding are called molecular chaperones, and as the name implies they have an important, but not well understood, assistive role in the process. Many molecular chaperones are essential for a cell’s survival. Some chaperones have been directly linked to the causes of genetic disorders involving misfolded proteins but others have been shown to be involved in slowing and preventing neurological diseases like Alzheimer’s. Peter Stirling’s research focuses on a protein called phosducin-like protein 3 (PhLP3), shown to be involved in facilitating protein folding as it interacts with an essential chaperone called CCT. Peter aims to understand how PhLP3 affects protein folding and what functional consequences the PhLP3-CCT interaction has. Peter’s research will help answer fundamental questions about how cells efficiently generate and maintain properly folded proteins, which will ultimately help to better understand what is happening in a cell when protein folding is disordered. His results may eventually lead to better treatment for diseases associated with protein misfolding.
Novel photoactive biomolecules: A photosensitive purine based drug release strategy and new methodology for generating PET labeled biomolecules
Medical imaging techniques such as X-rays, CT scans and MRIs, are widely used tools for diagnosing injury and illness. These tools provide a “”picture”” of bones, organs, muscles, tendons, nerves and cartilage, including any abnormalities. A new and evolving imaging technique called positron emission tomography, or PET scanning, provides additional details by creating a three dimensional image or map of functional processes in the body. By injecting radiolabelled molecules into the bloodstream, and then tracing their path and interactions, researchers and doctors can observe and map metabolic activity within various organs of the body. Photodynamic therapy (PDT) which is used in the treatment of psoriasis and certain cancers is similar to PET scanning in that photodynamic molecules (photosensitizers) are injected into the bloodstream. When the tissue to be treated is exposed to special light, the photosensitizers are activated, leading to a destructive action which kills abnormal cells. Richard Ting’s research is focused on examining and developing novel molecules, with potential application for both PET scanning techniques and photodynamic therapy. He aims to design a new class of molecules that would expand the limited amount of agents that can be imaged during PET scanning. In addition, he is researching a new class of molecules that could be used to improve the processes involved in photodynamic therapy.
Vascular endothelial growth factor induces endothelial cell hyperpermeability to low density lipoproteins in atherosclerotic disease
Coronary artery disease (CAD) and transplant associated-CAD are caused by a reduction or complete blockage of blood flow in blood vessels of the heart, which results in tissue death due to lack of oxygen. CAD is the leading cause of heart attacks, and transplant associated-CAD is the leading cause of organ failure one year after transplantation. Both diseases are characterized by abnormalities in blood vessel walls – abnormalities that result in the accumulaton of lipids and other blood components inside vessel walls. This causes them to thicken which acts to constrict blood flow. The endothelium is a blood vessel lining that serves as a barrier between the blood and tissue and also has a role in directing the transport of ions, lipids and proteins. Previous research has shown that vascular endothelial growth factor (VEGF), one of the most potent inducers of vascular permeability, is upregulated in these diseases. Brian Wong is working to determine the specific mechanisms by which VEGF induces this effect. He hypothesizes that the abnormal production of VEGF in CAD and transplant associated-CAD compromises endothelial barrier function, resulting in the increased passage of lipids and proteins into the vessel wall. Ultimately, he hopes to determine the therapeutic potential of blocking VEGF production in order to reduce lipid entry and accumulation in the vessel wall and prevent these diseases.
Biochemical and structural characterization of bacterial type III secretion system components
Harmful bacteria are becoming much more resistant to the currently available antibiotics, a situation that poses a serious threat to public health. The development of new and more effective ways of protecting against these increasingly dangerous (and antibiotic resistant) microbes requires a thorough understanding of the molecular mechanisms through which they cause disease. The bacterial type III secretion system (TTSS) is a complex mechanism that controls how bacterial proteins are transfered into human cells, a process that is essential to the disease-causing capabilities of a large number of pathogens, including Salmonella and pathogenic E.coli. Although many components of the TTSS have been identified, exactly how this secretion system is assembled and how virulence proteins (toxins) are delivered into target cells remains poorly understood. With support from a 2002 MSFHR Trainee Award, Calvin Yip successfully described the first high resolution structure of an extracellular component of the TTSS. Now funded for a second time, he is working to further characterize its structure and function. This work will help answer fundamental questions about the biochemical and structural characterization of TTSS, and may facilitate the design of new classes of drugs to combat a broad range of infectious agents.
Functional analysis of interferon inducible protein 10 gene in Coxsackievirus B3-induced myocarditis
Coxsackievirus B3 (CVB3) is the leading cause of viral myocarditis, an inflammation that can so severely damage the heart that a heart transplant becomes the only treatment option. Previous studies have identified 28 up – or down – regulated genes in CVB3-infected mouse hearts, but the functions and mechanisms of the host gene regulation in the progression of CVB3-induced myocarditis are not clear. Ji Yuan is further analyzing the role of host gene alteration in viral myocarditis by investigating the IP10 gene, believed to be the most crucial up-regulated gene. Her objective is to define the functional role of IP10 and trace the cascade of events precipitated by its up-regulation which result in major damage to the heart. By conducting these experiments, she will not only have a better understanding of the molecular mechanisms of viral myocarditis, but also may discover potential targets for gene therapy or new diagnostic tests for this heart disease.