Jan Ehses is conducting research that may contribute to improved treatment of type 2 diabetes, a form of the disease that occurs most frequently in adults and obese individuals. Ehses has a particular focus on glucose-dependent insulinotropic polypeptide (GIP), a potent hormone that accounts for at least 50 per cent of the insulin secreted from the pancreas following a meal. Studies have consistently shown that GIP’s ability to cause insulin secretion is compromised in type 2 diabetes. Using state-of-the-art technology, Ehses is investigating the hypothesis that GIP affects tissues through complex intracellular networks, and that the imbalances in metabolism associated with diabetes may affect this transfer of genetic material important for regulation of insulin production. Ultimately, the goal is to provide a map of the numerous ways GIP affects the whole body, leading to information that can be applied to treatment of type 2 diabetes.
Year: 2001
Cardiac Myocyte Apoptotic and Anti-Apoptotic Signalling Pathways Following Coxsackievirus B3 Infection
Mitra Esfandiarei has a specific goal: making a significant contribution to treatment of myocarditis (inflammation of the heart muscle) induced by a type of enterovirus (virus that comes into the body through the gastrointestinal tract). One such virus, coxsackievirus B3 (CVB3), causes severe cardiac and pancreatic diseases by directly injuring and killing heart muscle cells. In many cases, CVB3-infected myocarditis leads to cardiomyopathy (destruction of the heart muscle), for which the only available treatment is heart transplantation. Esfandiarei is studying how heart muscle cells can survive in the face of infection by CVB3. She hopes the research will enable novel treatment for viral-induced myocarditis and other cardiac conditions.
Synthesis and Evaluation of a Novel Class of Glycosidase Inhibitors for the Treatment of Type-2 Diabetes
Ahmad Ghavami’s PhD research involved a rare South Asian plant containing compounds that could be helpful in the treatment of type 2 diabetes. The Salacia reticulata climbing plant has been used for centuries in treatment of diabetes in Sri Lanka and India. Researchers have isolated compounds from the plant and demonstrated their effectiveness in inhibiting glycosidases, the enzymes that break down starch into smaller sugars, and finally into glucose. Using the compounds to inhibit these enzymes in people with type 2 diabetes could lower blood glucose concentration, which is critical in treatment of the disease. Ahmad and his colleagues designed a method to synthetically produce the plant’s compounds, together with the next generation analogues, and they tested the inhibitory effects on a wide range of enzymes. More importantly, in vivo studies with rats have shown effective control of blood glucose levels with use of Ghavami’s compounds. Results from the study confirm the effectiveness of the method for designing and synthesizing a new class of molecules that function as glycosidase inhibitors, which can control the breakdown of carbohydrates. These findings were patented, with Ahmad listed as part inventor, and were responsible for securing venture capital and the formation of a spin-off company, Mimos Therapeutics, Inc.
The Role of Homeobox Transcription Factors in Hematopoietic Stem Cell Function
For her Master’s research, Rhonna Gurevich studied the prevention of apoptosis (programmed cell death) in cardiac cells. Now she’s examining the genes that transform normal blood cells into malignant ones in leukemia patients. Gurevich is focusing on hematopoietic stem cells, which can self-renew to produce more stem cells with non-specific function or divide to create highly specialized cells to replace others that die or are lost. Maintaining the balance between stem cell self-renewal and division is a tightly controlled process. Gurevich is investigating how certain genes regulate hematopoietic stem cells, and specifically, how they may cause leukemia by disrupting the normal balance of cell renewal and division. She hopes that increasing knowledge of these genetic alterations can enable development of drugs to treat and potentially cure leukemia patients.
The characterization of bone marrow-derived mast cells (BMMCs) from SH2-containing inositol 5'-phosphatase (SHIP) knock-out mice
In 1996, Dr. Gerald Krystal’s lab identified and cloned a protein named SHIP. Janet Kalesnikoff, a doctoral student studying with Krystal, is examining how SHIP regulates mast cell function. Mast cells are activated by a number of different antigens/allergens, which bind to IgE antibodies on the surface of mast cells. IgE-induced mast cell activation results in the release of chemicals (eg. histamine) which are responsible for the common symptoms of allergic reactions such as hay fever and asthma. Studies in Dr. Krystal’s lab have revealed that SHIP negatively regulates the process of mast cell activation. She hopes this research will ultimately increase the understanding of SHIP’s role in mast cell function and reveal way to reduce the symptoms associated with allergic disease.
Structural Determinants of Kvl.5 Inactivation
Harley Kurata wants to contribute to the development of highly specific drugs with low toxicity for treating arrhythmia (irregular heartbeat). He’s focusing on potassium channels, the proteins that play a critically important role in regulating heartbeat. Because it is difficult to study potassium channels in isolated human heart cells, his research involves cloning genes to create these proteins in the laboratory. Kurata’s goal is to reveal how individual parts of the potassium channels are involved in regulating the channels’ function. He hopes the results can be applied to evaluation of current or potential anti-arrhythmia drugs. He also hopes that studying the effects of drugs on individual potassium channels will lead to new and more effective drugs to regulate irregular heartbeat.
Anticancer Drug Penetration into Solid Tumors
Solid tumours consist of a complex network of blood vessels surrounded by normal and malignant cells. They pose a particular challenge in the effort to develop anti-cancer drugs because malignant cell growth results in the development of regions in solid tumours that are resistant to radiation therapy. Anti-cancer drugs must overcome the barriers this environment poses, but there are currently no standard techniques for assessing a drug’s penetration in tumours. Alastair Kyle is addressing that gap by studying two techniques to examine the penetration of existing and new anti-cancer drugs. A better understanding of drug penetration in solid tumours could lead to the development of drugs that are more effective in entering the tumour. It could also lead to new insights into ways of modifying the tumour itself to make it more susceptible to specific cancer drugs.
Transgenic mouse models of congenital malignancies via expression of the ETV6-NTRK3 oncoprotein
During his Master’s research Christopher Lannon studied sensitivity to chemotherapy in adult and pediatric leukemias. Now Lannon is focusing on childhood cancers, which are biologically distinct from adult cancers and therefore present unique and interesting research challenges. He’s investigating a childhood tumour known as congenital fibrosarcoma (CFS). Several pediatric tumours, including CFS, are characterized by the fusion of two normal genes to form an abnormal fusion gene. Lannon aims to understand why this rearrangement of genetic material leads to malignant childhood tumours, with the goal of developing a mechanism to block the fusion.
Temperature Dependence of the Cardiac Sodium Calcium Exchanger
Mortality associated with open-heart surgery is two to three times higher in newborns than in adults. Christian Marshall believes this is due to a lack of knowledge about heart function in newborns, including how the neonatal heart responds to surgery. He’s focusing, in particular, on the inability of newborn heart cells to control calcium levels. When unregulated, calcium can initiate destructive events leading to cell death. Marshall is examining the effects of changes in temperature on the sodium-calcium exchanger (NCX), a protein in the heart cell membrane that is key to calcium regulation. Since surgeons need to reduce the temperature of the heart to perform open-heart surgery, and much of the cell damage occurs when warming the heart after surgery, Marshall is seeking a better understanding about temperature effects on NCX. He hopes this will reveal ways to reduce cell death during heart surgery and contribute to a better survival rate for these tiny patients.
The Role of the Rap1 GTPase in B Lymphocyte Migration and Adhesion
Sarah McLeod is examining the role of a protein, Rap 1 GTPase, in regulating essential cells in the immune system. In her previous research, McLeod discovered that this protein activates after B cells bind with antigens (substances that stimulate an immune response). Now McLeod is furthering that research by studying whether activation of the protein regulates the B cell activity, which enables the cells to produce antibodies for defense against harmful microbes and other infectious agents. Determining the overall function of Rap 1 in B cells and understanding how the protein regulates B cell adhesion and migration may provide insights into how these processes are regulated in B cells and other cell types.