Targeting To Mitochondria Of Tail-Anchored Proteins. Defining The Molecular Apparatus Of Targeting.
Funder
National Health and Medical Research Council
Funding Amount
$254,751.00
Summary
The cells of the body have an intricate and dynamic internal architecture, with the components (proteins, lipids, and nucleic acids) of the cell carefully arranged. It is widely viewed that just how each component finds its place in the cell, the cellular adressing system, is of critical importance. This was recognized this year by the award of the Nobel Prize in Medicine to Dr. Gunter Blobel for his work on the signals that direct different proteins to their correct destination. One such destin ....The cells of the body have an intricate and dynamic internal architecture, with the components (proteins, lipids, and nucleic acids) of the cell carefully arranged. It is widely viewed that just how each component finds its place in the cell, the cellular adressing system, is of critical importance. This was recognized this year by the award of the Nobel Prize in Medicine to Dr. Gunter Blobel for his work on the signals that direct different proteins to their correct destination. One such destination is the mitochnondria, the particles in the cell that produce chemical energy. The work in this proposal is designed to define precisely the molecular apparatus that targets a group of proteins to mitochondria. This group, proteins that are inserted into the mitochondria at one end of the protein, includes a variety of critical proteins, including those that determine the life or death of a cell. We will define both the address contained within those proteins, and the machinery on the mitochondria that recognizes that address, and ensures that those proteins will become part of the mitochondria. This research has two applications. By understanding the address, we will be able to decode the vast amount genomic data that is being produced, to predict exactly which proteins are delivered to mitochondria. Secondly, by understanding the targeting machinery, we may begin to design molecules that can inhibit its function, and thus manipulate the delivery of those proteins that affect cell life and death.Read moreRead less
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
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 .
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.