The Structural Basis Of Ligand-Induced Activation Of The Insulin Receptor
Funder
National Health and Medical Research Council
Funding Amount
$640,825.00
Summary
We aim to understand how insulin binds to and activates its cell-surface receptor. This information has implications for the design of anti-diabetic agents targetted directly to the insulin receptor. Diabetes is a global health problem and is classified by the World Health Organization as an epidemic. The results also have implications for the insulin-like growth factor receptor system and the design of anti-cancer therapeutics directed towards it .
Identification Of Insulin Specific Signal Transduction Pathways In Adipocytes
Funder
National Health and Medical Research Council
Funding Amount
$451,980.00
Summary
Insulin resistance, which represents an inability of insulin to regulate metabolism in appropriate target tissues such as muscle and adipose tissue, 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 ....Insulin resistance, which represents an inability of insulin to regulate metabolism in appropriate target tissues such as muscle and adipose tissue, 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). In the present proposal we will pursue a number of strategies to dissect the signal transduction pathways that connect the insulin receptor to the movement of this glucose transporter. Identification of these molecules will provide the missing pieces to this important puzzle. Once solved we will have at our disposal a novel set of targets for designing drugs that will combat insulin resistant diseases.Read moreRead less
Molecular Determinants Of Subcellular Localisation And Function Of The Transmembrane 4 Superfamily Protein, PETA-3
Funder
National Health and Medical Research Council
Funding Amount
$322,911.00
Summary
Several years ago we identified the cell membrane protein PETA-3-CD151 based on its ability to cause activation of blood platelets, suggesting a role in thrombosis. More recently we found that the protein is present in a variety of tissues, although its distribution in those tissues is often restricted. It is abundant in a variety of cancer cells, and is present on tissue mast cells that mediate allergic reactions. PETA-3-CD151 forms complexes with molecules (integrins) that are associated with ....Several years ago we identified the cell membrane protein PETA-3-CD151 based on its ability to cause activation of blood platelets, suggesting a role in thrombosis. More recently we found that the protein is present in a variety of tissues, although its distribution in those tissues is often restricted. It is abundant in a variety of cancer cells, and is present on tissue mast cells that mediate allergic reactions. PETA-3-CD151 forms complexes with molecules (integrins) that are associated with cell adhesion and migration, and antibodies to this protein inhibit cell movement. Thus PETA-3-CD151 appears to be involved in cellular interactions that are critical for normal tissue development and function, and may be involved in several disease processes including cancer invasion and metastasis. The molecular basis of PETA-3-CD151 function is not understood and is the focus of this application.Read moreRead less
Regulation Of Hedgehog Signalling Through Intracellular Trafficking Events
Funder
National Health and Medical Research Council
Funding Amount
$220,500.00
Summary
The hedgehog signalling cascade plays a role in forming almost every organ of the body during development of an embryo. Perturbation of the function of key members of this pathway during embryonic development often results in death in utero or severe childhood abnormalities. In addition, disruption to this pathway also results in a range of cancers, most notably the extremely common skin cancer basal cell carcinoma. In this proposal we aim to investigate in detail the regulatory mechanisms which ....The hedgehog signalling cascade plays a role in forming almost every organ of the body during development of an embryo. Perturbation of the function of key members of this pathway during embryonic development often results in death in utero or severe childhood abnormalities. In addition, disruption to this pathway also results in a range of cancers, most notably the extremely common skin cancer basal cell carcinoma. In this proposal we aim to investigate in detail the regulatory mechanisms which operate to ensure that this complex pathway of interacting molecules functions correctly during embryonic development. By understanding how this regulation occurs we will gain valuable insight into how disruption of this pathway results in such a range of disease, as well as into how agents which modulate this pathway may potentially act in a therapeutic setting.Read moreRead less
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
Regulation Of Body Composition And Glucose Homeostasis By The Adaptor Protein Grb10.
Funder
National Health and Medical Research Council
Funding Amount
$617,256.00
Summary
Resistance to the hormone insulin underlies the development of Type 2 Diabetes. Loss of muscle mass in the elderly contributes to insulin resistance. Recently we identified Grb10 as a new regulator of insulin action and muscle mass. In this proposal, we aim to study how Grb10 affects development and growth of muscle and fat, and the underlying molecular mechanisms. This may lead to new strategies for improving body composition and treating the insulin resistance associated with Type 2 Diabetes.
Molecular, genetic and cellular analysis of melanisation in human pigmentation. This investigation examines variations in the genes that determine human skin pigmentation and are likely to be associated with skin cancer risk. Our research program will form the basis of future diagnostics based on major genes that determine a persons skin type. Current skin cancer prevention strategies rely predominantly on broad spectrum campaigns that are aimed at increasing the general community awareness of ....Molecular, genetic and cellular analysis of melanisation in human pigmentation. This investigation examines variations in the genes that determine human skin pigmentation and are likely to be associated with skin cancer risk. Our research program will form the basis of future diagnostics based on major genes that determine a persons skin type. Current skin cancer prevention strategies rely predominantly on broad spectrum campaigns that are aimed at increasing the general community awareness of the damaging effects of ultraviolet (UV) radiation. A better understanding of the genetic basis of UV-sensitive skin types will greatly enhance the targeting of such skin cancer-prevention campaigns, provide an understanding of changes that occur in skin pathology, and the mechanisms of sun induced tanning.Read moreRead less
Combined genetic and cellular analysis of melanisation to study variation in human pigmentation. This investigation examines variations in the genes that are important determinants of human skin pigmentation and are likely to be associated with skin cancer risk. Our research program will form the basis of future diagnostics based on major genes that determine a persons skin type. Current skin cancer prevention strategies rely predominantly on broad spectrum campaigns that are aimed at increasi ....Combined genetic and cellular analysis of melanisation to study variation in human pigmentation. This investigation examines variations in the genes that are important determinants of human skin pigmentation and are likely to be associated with skin cancer risk. Our research program will form the basis of future diagnostics based on major genes that determine a persons skin type. Current skin cancer prevention strategies rely predominantly on broad spectrum campaigns that are aimed at increasing the general community awareness of the damaging effects of UV radiation. A better understanding of the genetic basis of UV-sensitive skin types will greatly enhance the targeting of such skin cancer-prevention campaigns, provide an understanding of changes that occur in skin pathology, and the mechanisms of sun induced tanning.Read moreRead less
Parallel genetic and cellular analysis of melanogensis: A new paradigm to study variation in pigmentation. This is the first attempt to characterise the differences in human pigmentation using a combined genetic and cellular analysis of melanogenesis. We have the ability to culture the pigmenting cells of the human epidermis and hair follicles called melanocytes from individuals of defined genotype. This will allow us to correlate mutations in melanosomal proteins with functional defects withi ....Parallel genetic and cellular analysis of melanogensis: A new paradigm to study variation in pigmentation. This is the first attempt to characterise the differences in human pigmentation using a combined genetic and cellular analysis of melanogenesis. We have the ability to culture the pigmenting cells of the human epidermis and hair follicles called melanocytes from individuals of defined genotype. This will allow us to correlate mutations in melanosomal proteins with functional defects within the cells in culture using live cell imaging, electron microscopy and biochemical analysis. This will provide a molecular basis to explain the pigmentary characteristics of individuals allowing prediction and diagnosis of their photosensitivity with important implications for skin cancer risk.Read moreRead less