The regulated movement of membrane receptors and ligands between the cell surface and intracellular compartments is vital to many cellular operations, including communication between cells and their environment. However, the molecular details of these sorting events remain poorly defined. Determination of the mechanisms that control the cellular distribution of receptors is critical for understanding normal cellular processes and in pathological processes like tumorigenesis.
Novel G-protein Coupled Receptor Interactions And Complexes With Distinct Function And Pharmacology
Funder
National Health and Medical Research Council
Funding Amount
$246,760.00
Summary
G protein coupled receptors (GPCRs) are the target in the human body for most of today's medicines. Almost all pharmaceutical companies market drugs that are GPCR agonists or antagonists aimed at diverse disease states. Our research is focused on the molecular basis of drug recognition and signalling by GPCRs. We use genetic engineering techniques to create new receptors and mutant receptors in order to identify the functional domains of these signalling molecules. We have recently established a ....G protein coupled receptors (GPCRs) are the target in the human body for most of today's medicines. Almost all pharmaceutical companies market drugs that are GPCR agonists or antagonists aimed at diverse disease states. Our research is focused on the molecular basis of drug recognition and signalling by GPCRs. We use genetic engineering techniques to create new receptors and mutant receptors in order to identify the functional domains of these signalling molecules. We have recently established a novel approach based on proximity-dependent fluorescent technologies to explore receptor interactions and have described the formation of functional G-protein coupled complexes in living cells. This project is to discover new receptor combinations which could potentially affect signalling pathways and redirect cellular responses. Investigation of the mechanisms involved in turning on and off the body s response to stimuli would provide valuable information for drug design and treatment of GPCR-related conditions. We have chosen to use two GPCRs as models for our study of the mechanisms controlling receptor driven cellular responses and the interactions between cellular components-proteins behind this control. Firstly, the gonadotropin releasing hormone receptor (GnRHR), a protein located in the pituitary which is pivotal in the control of reproduction and secondly, the thyrotropin releasing hormone receptor (TRHR), similarly located and involved in modulating thyroid and metabolic function. We will investigate the way these receptors interact with other cellular proteins in order for them to function. Ultimately this will provide a better understanding of how these clinically important proteins function and pave the way for the development of clinical applications that target these receptor systems, resulting in the effective treatment of a wide range of conditions and diseases, including pain, migraine, certain forms of cancer, neurological and reproductive disorders.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
The Regulation Of PI 3-kinase Second Messenger Molecules, PtdIns(3,4)P2 And PtdIns 3-P.
Funder
National Health and Medical Research Council
Funding Amount
$406,980.00
Summary
Cells respond to the external environment, hormones, and growth factors by generating messages inside the cell that send a signal to the nucleus that stimulates cell growth. One such signalling network is that produced by membrane lipids known as phosphoinositides. Enzymes that produce these signals are known as kinases. There has been considerable interest in the PI 3-kinase as the signals generated by this enzyme are increased in many human cancers. Inherited cancer syndromes have been describ ....Cells respond to the external environment, hormones, and growth factors by generating messages inside the cell that send a signal to the nucleus that stimulates cell growth. One such signalling network is that produced by membrane lipids known as phosphoinositides. Enzymes that produce these signals are known as kinases. There has been considerable interest in the PI 3-kinase as the signals generated by this enzyme are increased in many human cancers. Inherited cancer syndromes have been described that have lost the ability to switch off PI 3-kinase signals. The current project aims to investigate a recently identified enzyme called the 4-phosphatase that has the ability to terminate PI 3-kinase signals. Recent studies have shown this enzyme regulates cell growth. In addition key experiments have shown the enzyme is important as it may regulate certain strains of bacterial infection. This research proposal aims to investigate how the enzyme works to regulate these growth promoting signals. This may help us develop novel therapeutic strategies to control cell growth.Read moreRead less