The project aims to understand how a factor responsible for the production of a type of white blood cell interacts with its receptor. If we knew the molecular details of how this factor works then we would be able to control better diseases, such as osteoporosis and arthritis, where such cells can play havoc by destroying tissue. The project also has implications for certain leukaemias which lose growth control mechanisms in response to this factor.
Analysis Of Intracellular Signalling And Biological Activities Of The GM-CSF Receptor Family Using Constitutive Mutants
Funder
National Health and Medical Research Council
Funding Amount
$505,699.00
Summary
The cytokines GM-CSF, IL-3 and IL-5 stimulate the growth and actions of a wide range of blood cells. Each binds to a receptor on the cell surface which then triggers the generation of a number of signals inside the cell; it is these signals that are responsible for the cytokine?s actions. We have previously generated a panel of constitutive mutant forms of the beta subunit which is shared by the GM-CSF, IL-3 and IL-5 receptors. These constitutive mutants trigger signals even in the absence of th ....The cytokines GM-CSF, IL-3 and IL-5 stimulate the growth and actions of a wide range of blood cells. Each binds to a receptor on the cell surface which then triggers the generation of a number of signals inside the cell; it is these signals that are responsible for the cytokine?s actions. We have previously generated a panel of constitutive mutant forms of the beta subunit which is shared by the GM-CSF, IL-3 and IL-5 receptors. These constitutive mutants trigger signals even in the absence of the cytokine; importantly, the different mutants appear to trigger only a subset of the signals generated by the normal receptor. The aim of this project is to use our panel of constitutive beta subunit mutants to determine how the GM-CSF, IL-3 and IL-5 receptors generate signals inside the cell and how these signals lead to the various biological actions of the receptors on blood cell growth and maturation. Findings from this research will be relevant to the understanding and treatment of diseases which involve abnormal growth or function of blood cells such as leukaemia and inflammatory diseases.Read moreRead less
Molecular Mechanisms Underlying G Protein Coupled Receptor Signaling
Funder
National Health and Medical Research Council
Funding Amount
$596,956.00
Summary
The maintenance of optimum health and function of living cells, and consequently that of the whole organism, depends on how cells respond to a multitude of physical and chemical stimuli that continually bombard them. The majority of the chemical stimuli such as hormones and neurotransmitters impart their actions not by directly entering the cell, but instead, by binding to a specific receiver protein at the cell surface called a receptor. In one class of such receptors called G protein-coupled r ....The maintenance of optimum health and function of living cells, and consequently that of the whole organism, depends on how cells respond to a multitude of physical and chemical stimuli that continually bombard them. The majority of the chemical stimuli such as hormones and neurotransmitters impart their actions not by directly entering the cell, but instead, by binding to a specific receiver protein at the cell surface called a receptor. In one class of such receptors called G protein-coupled receptors, the transmission of the message to the interior of the cell involves yet another protein called G protein. These receptors are the most abundant type of cell surface receptors and form the targets for nearly 50% of currently used therapeutic drugs. It is, therefore, extremely important to unravel how each of these components works, and in particular to know how they work in living cells. This project utilizes state-of-the-art methodologies to examine interactions between receptors and their cognate G proteins, in living cells and in real-time. The work will answer fundamental questions about the nature of G protein-coupled receptor signaling and will aid in the future development of more effective therapeutic agents.Read moreRead less
Regulators Of G Protein Signalling On The Golgi Complex
Funder
National Health and Medical Research Council
Funding Amount
$666,116.00
Summary
The secretion of proteins from cells involves a host of regulatory and signalling proteins. G proteins, signal transducers, located on the Golgi membranes, participate in the budding of transport vesicles in the secretory pathway. A newly-discovered family of Regulators of G Protein Signalling (RGS) proteins perform the critical function of turning off signals generated by G proteins. RGS proteins are powerful, but as yet, ill-defined regulatory molecules. In this study we will identify and char ....The secretion of proteins from cells involves a host of regulatory and signalling proteins. G proteins, signal transducers, located on the Golgi membranes, participate in the budding of transport vesicles in the secretory pathway. A newly-discovered family of Regulators of G Protein Signalling (RGS) proteins perform the critical function of turning off signals generated by G proteins. RGS proteins are powerful, but as yet, ill-defined regulatory molecules. In this study we will identify and characterize RGS proteins in macrophages that are located on Golgi membranes and help to regulate cytokine secretion and other immune functions. More detailed studies on selected RGS proteins will include mutational analysis of functional domains within the proteins and identification of other proteins that interact with RGS proteins. Overall these studies will lead us to understand how specific RGS proteins interact with G proteins and other molecules to regulate signalling in the secretory pathway. Anomalies in cell signalling have severe consequences in a variety of diseases and can cause cancer. Similarly, abnormal secretion in cells contributes to inflammation, diabetes and other disease processes. Information forthcoming from our studies on RGS proteins will have wide-reaching implications and the potential to reveal new targets for therapeutics in these diseases.Read moreRead less
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