Dissecting A Serial Killer: Investigating The Degranulation Pathways In Cytotoxic Lymphocytes
Funder
National Health and Medical Research Council
Funding Amount
$604,459.00
Summary
When cells of the human body become cancerous or infected with virus, the body's immune system engages cytotoxic lymphocytes, known as "killer cells", that secrete an auxiliary of toxic proteins to eliminate these cells. The aim of this study is to investigate the mechanisms by which these critical immune cells accomplish this task. Importantly, humans who are genetically lacking in critical constituents of the cytotoxic lymphocyte are less able to fight off a viral infection and may be at a hig ....When cells of the human body become cancerous or infected with virus, the body's immune system engages cytotoxic lymphocytes, known as "killer cells", that secrete an auxiliary of toxic proteins to eliminate these cells. The aim of this study is to investigate the mechanisms by which these critical immune cells accomplish this task. Importantly, humans who are genetically lacking in critical constituents of the cytotoxic lymphocyte are less able to fight off a viral infection and may be at a higher risk of developing cancer.Read moreRead less
Macrophages are white blood cells that provide front line defence against infection by initiating inflammatory responses by ingesting or phagocytosing microbes and by releasing soluble messengers (cytokines) to recruit other immune cells. These defensive functions require extensive trafficking of proteins within the macrophages. Protein trafficking is orchestrated in part by a family of membrane fusion proteins called SNAREs. By defining the relevant SNAREs, we have recently discovered a much ac ....Macrophages are white blood cells that provide front line defence against infection by initiating inflammatory responses by ingesting or phagocytosing microbes and by releasing soluble messengers (cytokines) to recruit other immune cells. These defensive functions require extensive trafficking of proteins within the macrophages. Protein trafficking is orchestrated in part by a family of membrane fusion proteins called SNAREs. By defining the relevant SNAREs, we have recently discovered a much acclaimed and novel pathway that allows efficient, combined cytokine secretion and phagocytosis in macrophages. Our studies proposed here will now expand on this discovery by comparing the phagocytic process, in terms of SNARE-mediated membrane and cytokine trafficking, for a wide range of microbes, highlighting differences that could provide new avenues for drug development. Moreover, since our strategy of using SNAREs to investigate and map trafficking pathways has proven so successful, we will now launch a major large-scale initiative to study ALL SNARE-mediated trafficking pathways in macrophages using a discovery pipeline of assays, including live cell imaging, we have developed. This will provide valuable information on many SNAREs including those associated with disease, and will elucidate trafficking pathways governing all macrophage actions in immunity, including cytokine secretion and antigen presentation. All of these pathways are highly relevant to current drug targets being used clinically or studied in inflammatory disease and for the development of vaccines.Read moreRead less
Dysferlinopathy: A Genetic Disease Sheds Light On Membrane Repair For Muscle And Cardiac Injury
Funder
National Health and Medical Research Council
Funding Amount
$782,806.00
Summary
Muscles are damaged all of the time, as we stretch and contract them, but we don't fully understand how they repair themselves. We are studying the molecular steps taken by a muscle cell to repair membrane damage. Our research will provide valuable insights into how to treat muscular dystrophy and other conditions characterised by membrane damage to cells, such as heart attack and stroke.
Dysferlin Coordinates Membrane Repair For Skeletal And Cardiac Injury
Funder
National Health and Medical Research Council
Funding Amount
$459,270.00
Summary
Muscles are damaged all of the time, as we stretch and contract them, but we don't fully understand how they repair themselves. We are studying the molecular steps taken by a muscle cell to repair membrane damage. Our research will provide valuable insights into how to treat muscular dystrophy and other conditions characterised by membrane damage to cells, such as heart attack and stroke.
Analysis Of The Role Of Vesicle Docking/Fusion Proteins In Trafficking Of The Glut4 Glucose Transporter In Adipocytes
Funder
National Health and Medical Research Council
Funding Amount
$212,036.00
Summary
The objective of these studies is to understand the molecular mechanisms that are involved in the control of blood glucose levels by the hormone insulin. Elevated blood glucose levels following a meal stimulate the pancreas to release insulin into the circulation. Insulin acts to reduce blood sugar levels by stimulating the uptake of glucose into fat and muscle and suppressing glucose production by the liver. Defects in insulin action in these tissues are the primary cause of Type II diabetes. T ....The objective of these studies is to understand the molecular mechanisms that are involved in the control of blood glucose levels by the hormone insulin. Elevated blood glucose levels following a meal stimulate the pancreas to release insulin into the circulation. Insulin acts to reduce blood sugar levels by stimulating the uptake of glucose into fat and muscle and suppressing glucose production by the liver. Defects in insulin action in these tissues are the primary cause of Type II diabetes. The debilitating effects of Type II diabetes, the dramatic increase its incidence, and the expense of treating the symptoms of diabetic complications have lead to the realization that the disease represents a major health problem requiring substantial research and development efforts. The project will focus on insulin regulation of glucose uptake in fat cells. Insulin promotes glucose uptake into fat by activating an intracellular signaling pathway that triggers the translocation of a unique glucose transporter protein (Glut4) from storage sites inside the cell to the cell surface. Glut4 translocation is mediated by small membrane vesicles that function to sequester the glucose transporter inside cells in the absence of insulin, and to shuttle Glut4 to the cell surface in response to the hormone. Despite the central importance of this event to the maintenance of normal blood glucose levels, it is poorly understood. The studies will be directed towards investigating the cellular machinery involved in the latter stages of insulin-stimulated glucose uptake- the vesicle-mediated delivery of Glut4 to the cell surface. The objective of these studies is to better understand the molecular basis for Glut4 translocation, and regulation by the insulin signaling cascade. Accomplishment of this goal may suggest potential drug intervention strategies aimed at enhancing insulin-stimulated Glut4 translocation and promoting improved control of blood glucose levels in Type II diabetes.Read moreRead less
Insulin resistance (the inability of ordinarily insulin-sensitive tissues such as muscle and adipose tissue to respond to insulin) contributes to a number of diseases including diabetes and obesity. A key metabolic step in these tissues is the uptake of glucose from the blood stream. This step is accelerated by insulin thus allowing efficient clearance of glucose from the bloodstream after a meal. Our laboratory has played a major role in showing that insulin regulates glucose uptake into muscle ....Insulin resistance (the inability of ordinarily insulin-sensitive tissues such as muscle and adipose tissue to respond to insulin) contributes to a number of diseases including diabetes and obesity. A key metabolic step in these tissues is the uptake of glucose from the blood stream. This step is accelerated by insulin thus allowing efficient clearance of glucose from the bloodstream after a meal. Our laboratory has played a major role in showing that insulin regulates glucose uptake into muscle and adipose tissue by stimulating the movement of a glucose transport protein from inside the cell to the cell surface (see http:--www.imb.uq.edu.au-groups-james-glut4 for an animated description of this process). The purpose of this proposal is to dissect the molecular mechanisms by which this glucose transporter can be held inside the cell in the absence of insulin and then allowed to be released from this site moving to the surface in the presence of insulin. Our studies over the past 5 years have brought us much closer to understanding this process in detail. The identification of the molecules responsible for this regulatory step will not only aid our understanding of this process but it will also provide a valuable target for development of therapeutic agents that can be used to combat insulin resistance.Read moreRead less
Obesity and diabetes are increasing in our community at an alarming rate. When one considers that Diabetes is a major cause of heart disease, stroke and kidney disease these diseases represent one of the most threatening for the future health of our nation. At the heart of these diseases is a disorder known as insulin resistance, or the inability of insulin to function correctly. The explosion in biological outcomes over the past decade has brought us closer than ever before to solving some of t ....Obesity and diabetes are increasing in our community at an alarming rate. When one considers that Diabetes is a major cause of heart disease, stroke and kidney disease these diseases represent one of the most threatening for the future health of our nation. At the heart of these diseases is a disorder known as insulin resistance, or the inability of insulin to function correctly. The explosion in biological outcomes over the past decade has brought us closer than ever before to solving some of the key questions associated with this problem. This proposal represents an exciting step forward in this area because our recent research combined with information from our international colleagues have led us to propose a new concept concerning the mechanism of insulin action. In this proposal we have formulated a series of molecular experiments to test this hypothesis which if correct will both change the way we think about this problem and provide new prospects for therapeutic design.Read moreRead less
Insulin resistance (the inability of ordinarily insulin-sensitive tissues such as muscle and adipose tisse to respond to insulin) contributes to a number of diseases including diabetes and obesity. A key metabolic step in these tissues is the uptake of glucose from the blood stream. This step is accelerated by insulin thus allowing efficient clearance of glucose from the bloodstream after a meal. Our laboratory has played a major role in showing that insulin regulates glucose uptake into muscle ....Insulin resistance (the inability of ordinarily insulin-sensitive tissues such as muscle and adipose tisse to respond to insulin) contributes to a number of diseases including diabetes and obesity. A key metabolic step in these tissues is the uptake of glucose from the blood stream. This step is accelerated by insulin thus allowing efficient clearance of glucose from the bloodstream after a meal. Our laboratory has played a major role in showing that insulin regulates glucose uptake into muscle and adipose tissue by stimulating the movement of a glucose transport protein from inside the cell to the cell surface. The purpose of this proposal is to dissect the molecular mechanisms by which this glucose transporter can be held inside the cell in the absence of insulin and then allowed to be released from this site moving to the surface in the presence of insulin. Our studies over the past 5 years have brought us much closer to understanding this process in detail. The identification of the molecules responsible for this regulatory step will not only aid our understanding of this process but it will also provide a valuable target for development of therapeutic agents that can be used to combat insulin resistance.Read moreRead less
Dissection Of Insulin Regulated Phosphorylation In The Adipocyte
Funder
National Health and Medical Research Council
Funding Amount
$303,510.00
Summary
Obesity and diabetes are increasing at an alarming rate throughout the world. These diseases are part of a constellation of disorders that includes cardiovascular disease and kidney disease, which are collectively referred to as the metabolic syndrome. A disorder referred to as insulin resistance is at the heart of the metabolic syndrome. This represents the inability of insulin to function correctly in target cells like muscle and fat. In this project we are attempting to undertake a large scal ....Obesity and diabetes are increasing at an alarming rate throughout the world. These diseases are part of a constellation of disorders that includes cardiovascular disease and kidney disease, which are collectively referred to as the metabolic syndrome. A disorder referred to as insulin resistance is at the heart of the metabolic syndrome. This represents the inability of insulin to function correctly in target cells like muscle and fat. In this project we are attempting to undertake a large scale effort to understand the complex circuitry that gets turned on within cells when they become exposed to insulin. This project involves a collaboration between the Garvan Institute and the University of New South Wales Mass Spectrometry Facility allowing us to bring a combination of very sophisticated technologies to bear on this very significant health care problem. This project will provide major new insights into our understanding of insulin action yielding new possibilities for therapeutic development.Read moreRead less