Calvin Yip

Lab Website

“The entire cell can be viewed as a factory that contains an elaborate network of interlocking assembly lines, each of which is composed of a set of large protein machines.” – Bruce Alberts

Most essential cellular processes are carried out by large multi-protein complexes. While recent research has improved our understanding of the identity and composition of the multitude of protein complexes in the cell, we have only limited knowledge of the overall architecture and mechanisms of action of these “protein machines”. Our laboratory is interested in investigating the structure, organization, function, and regulatory mechanisms of these protein machines, with an emphasis on complexes involved in cell signal transduction. We use advanced single particle electron microscopy (EM) methods, yeast genetics, and other biochemical and structural approaches to achieve this objective.

Susan Clee

Lab Webpage

The rapidly increasing prevalence of obesity and diabetes world-wide, particularly in children, has been rightly described as a health epidemic. In the ‘Laboratory of the Genetics of Obesity and Diabetes’ we use genetics as a tool to gain insight into novel pathways promoting obesity and diabetes. Genetic factors largely determine which individuals will develop obesity and/or diabetes in the context of a lifestyle of diets high in fat and carbohydrate and reduced exercise. However, the identities of most of these factors, and thus the underlying molecular alterations, are unknown. Years of analyses of the genes and pathways that have functions related to our understanding of the disease process have identified very few genetic factors that determine obesity or diabetes susceptibility in the general population.

Eric Jan

Lab Website

The regulation of gene expression at the translational level is fundamental for normal cellular homeostasis and survival. Because control of translation is relatively quick and efficient, cells can regulate gene expression quickly in response to environmental stresses. During some cellular stresses such as viral infection, endoplasmic stress, and apoptosis, the cell adapts by inhibiting overall protein synthesis. However, it is apparent that a subset of mRNAs is translated under these conditions. These mRNAs, in general, encode for proteins that are important for the cell to adapt to the environmental stress. The identification of these specialized mRNAs is crucial in our understanding of fundamental gene expression mechanisms and how cells respond to stress and viral infection. The primary areas of the lab are:

A) To examine the mechanisms by which overall protein synthesis is shutoff in response to cellular stress. ER stress and hypoxia are common stresses that occur during the progression of diseases such as cancer and diabetes. By pinpointing the translational control mechanisms underlying these stresses, we will get a better understanding of how cells respond to stress and how these mechanisms may go awry during disease progression.

B) To identify mRNAs that are selectively translated during conditions when overall protein synthesis is shutoff and to elucidate how these specialized mRNAs can bypass the translational control block. Elucidating the translational control mechanisms of these specialized mRNAs is not only important for our overall understanding of gene expression during stress, but may also reveal novel targets for developing therapies against viral infections, stress and cancer.

Tim Kieffer

Lab Webpage

The ‘Laboratory of Molecular and Cellular Medicine’ consists of students (graduate & undergraduate), technicians and postdoctoral fellows dedicated to developing novel and innovative therapeutic approaches for diabetes.

The ‘Laboratory of Molecular and Cellular Medicine’ consists of students (graduate & undergraduate), technicians and postdoctoral fellows dedicated to developing novel and innovative therapeutic approaches for diabetes. Our research typically involves sophisticated molecular techniques and studies at the cellular and physiological level. We believe that gene and cell based therapies may be the medicine of the future.

In 1923, Canadians Banting, Macleod, Best and Collip shared the Nobel Prize for their discovery of insulin. For millions of people around the world, this was a life-saving discovery. However, insulin is not a cure for diabetes. A diagnosis of type 1 diabetes still means thousands of insulin injections and blood glucose tests every year. Moreover, as it is virtually impossible to maintain optimal blood glucose levels by insulin injections, patients still suffer from several debilitating complications and reduced life-span.

Transplantation of pancreatic islets has proven to be effective in controlling blood glucose levels in subjects with type 1 diabetes. The results demonstrate the potential to treat diabetes by transplanting as little as a teaspoon of insulin-producing cells. However, this procedure is dependent upon obtaining tissue from recently deceased individuals and currently requires the use of chronic immunosuppression.

In our Laboratory we are investigating a variety of approaches to achieve the same result, without relying on tissue from donors. Ideally, we would like to develop a therapy that uses the patient’s own cells. While their insulin producing beta-cells may be absent or dysfunctional, it is possible that we may be able to stimulate sufficient numbers of beta-cells to grow back, or generate new beta-cells from stem cells. Alternatively we may be able to genetically modify other cells in the body to produce insulin or other anti-diabetic factors automatically in a meal-dependent manner. The ‘Laboratory of Molecular and Cellular Medicine’ consists of students (graduate & undergraduate), technicians and postdoctoral fellows dedicated to developing novel and innovative therapeutic approaches for diabetes. Our research typically involves sophisticated molecular techniques and studies at the cellular and physiological level. We believe that gene and cell based therapies may be the medicine of the future.

In 1923, Canadians Banting, Macleod, Best and Collip shared the Nobel Prize for their discovery of insulin. For millions of people around the world, this was a life-saving discovery. However, insulin is not a cure for diabetes. A diagnosis of type 1 diabetes still means thousands of insulin injections and blood glucose tests every year. Moreover, as it is virtually impossible to maintain optimal blood glucose levels by insulin injections, patients still suffer from several debilitating complications and reduced life-span.

Transplantation of pancreatic islets has proven to be effective in controlling blood glucose levels in subjects with type 1 diabetes. The results demonstrate the potential to treat diabetes by transplanting as little as a teaspoon of insulin-producing cells. However, this procedure is dependent upon obtaining tissue from recently deceased individuals and currently requires the use of chronic immunosuppression.

In our Laboratory we are investigating a variety of approaches to achieve the same result, without relying on tissue from donors. Ideally, we would like to develop a therapy that uses the patient’s own cells. While their insulin producing beta-cells may be absent or dysfunctional, it is possible that we may be able to stimulate sufficient numbers of beta-cells to grow back, or generate new beta-cells from stem cells. Alternatively we may be able to genetically modify other cells in the body to produce insulin or other anti-diabetic factors automatically in a meal-dependent manner.

Jim Johnson

Lab Webpage

The Laboratory of Molecular Signalling in Diabetes is a dynamic team of individuals focused on understanding the causes of type 1 and type 2 diabetes at a molecular level.

The Laboratory of Molecular Signalling in Diabetes is a dynamic team of individuals focused on understanding the causes of type 1 and type 2 diabetes at a molecular level. Our studies are guided by the discovery of genes and associated gene networks linked to diabetes risk and by known risk factors that predispose individuals to diabetes. The common forms of both type 1 diabetes and type 2 diabetes appear to result from a combination of genetic and acquired factors, and both diseases are increasing in prevalence. Despite some major advances, we do not yet understand the root causes of diabetes.

We study the role of the insulin-secreting pancreatic beta-cell in type 1 diabetes, type 2 diabetes, and other rare forms of diabetes. We are particularly interested in determining the molecular signalling pathways that control the survival and function of these insulin-secreting cells. These signals represent the key to understanding the disease and designing rational treatments.

In order to understand these processes, we employ state-of-the-art techniques including: molecular imaging, molecular biology and in vivo studies. In many cases we examine the role of a particular gene from the single-cell level (where the exact mechanism of its action can be established) to the level of the whole organism (where its role in total body energy homeostasis can be evaluated).

In the Laboratory of Molecular Signalling in Diabetes, we believe fundamental science is essential to finding a cure to diabetes. The lab is filled with motivated, hard-working staff, students and post-doctoral fellows working toward this goal.

Christopher McIntosh

Lab Webpage

My research focuses on the modes of action of gastrointestinal hormones involved in the regulation of insulin secretion and fat metabolism, and the pathophysiological consequences of altered function in obesity and non-insulin dependent diabetes mellitus (NIDDM). This consists of the following areas of study:

A.  The GIP receptor and its signal transduction mechanisms
GIP (gastric inhibitory polypeptide, glucose-dependent insulinotropic polypeptide) is synthesized in the intestine and has two well characterized biological actions: inhibition of acid secretion (enterogastrone action) and the stimulation of insulin release (incretin effect) (1). We have cloned the pancreatic GIP receptor (2-3), and are studying the specific domains involved in ligand binding and signal-transduction using receptor chimeras (4) and point-mutated and truncated forms (5) of the receptor produced by site-directed mutagenesis. The possibility that there are different receptor subtypes in other tissues, which are involved in different actions, is also being investigated. We have recently identified a novel new pathway by which GIP acts on the pancreatic insulin-secreting beta cell that may be involved in the regulation of islet cell differentiation and mitogenesis.

B.  Changes in responsiveness to incretins in obesity and non-insulin dependent diabetes mellitus
Insulin secretion is altered in human obesity and NIDDM. Animal models of these conditions are being studied to determine the origin of altered responsiveness to GIP in these animals (7). We have recently shown that the expression of the GIP receptor in a Vancouver strain of the obese Zucker rat has greatly reduced expression of the GIP receptor and reduced signal-transduction (8). Such studies should provide clues as to the origins of the reduced sensitivity to incretins in the human disorders.

C.  The metabolism of incretins in normal and disease states
There is currently great interest in using incretins in the treatment of NIDDM in humans. We are defining the biologically active region of the GIP molecule (12-14) and attempting to develop long acting analogs. In addition, the alternative strategy of inhibiting DP IV, and thus increasing endogenous incretins, is being studied. In the studies with Probiodrug, Germany, one of these inhibitors has been shown to dramatically improve glucose tolerance in diabetic rats (14, 15), and is currently undergoing clinical trials.

Roger Brownsey

Lab Webpage

The research in the Brownsey Laboratory is directed to understanding the molecular mechanisms by which hormones bring about changes in cell metabolism and function. Our work is especially concentrated on the mechanism of insulin action on fatty acid synthesis and on the key lipogenic enzyme acetyl-CoA carboxylase. The effects of insulin on fat synthesis, like those on other pathways, occur very rapidly after the binding of the hormone to specific receptor proteins in the plasma membrane. This hormone-receptor complex induces a complex set of intracellular signals which result in changes in the properties of key metabolic regulatory proteins including glucose transporters, glycogen synthase, pyruvate dehydrogenase, hormone-sensitive lipase and acetyl-CoA carboxylase.