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
Characterisation Of A New Family Of Proteins Involved In Cell Signalling, RNA Metabolism And Cancer
Funder
National Health and Medical Research Council
Funding Amount
$200,880.00
Summary
We have discovered a novel RNA-binding protein (G3BP-2) that is involved in responding to external signals, such as growth factors, at the level of gene expression. Other RNA-binding proteins belonging to the same broad group of proteins are responsible for a host of disease states in mammals including mental retardation, myotonic dystrophy, Huntington?s disease and cancers. Considering the wealth of knowledge accumulated that implicates these proteins to human dysfunction surprisingly few of th ....We have discovered a novel RNA-binding protein (G3BP-2) that is involved in responding to external signals, such as growth factors, at the level of gene expression. Other RNA-binding proteins belonging to the same broad group of proteins are responsible for a host of disease states in mammals including mental retardation, myotonic dystrophy, Huntington?s disease and cancers. Considering the wealth of knowledge accumulated that implicates these proteins to human dysfunction surprisingly few of these RNA-binding proteins have been identified. We have shown that the novel protein discovered in our laboratory is perturbed in cancer and we are interested in characterising its putative role in cancer. The results established in our laboratory so far would indicate that generally, G3BP-2 is expressed in normal tissue and it expression changes in some cancers studied so far. Considering that G3BP-2 lies in a pathway known to be involved in cancer progression it is important to understand what effects the inappropriate expression of G3BP-2 may have on cancer progression and survival. This project is designed to characterise what signals the cell uses to control these proteins and in turn which genes these may effect. In this way we may be able to determine how external signals may effect tumour progression and on what genes this influence is expressed. It would be hoped that this project would increase our understanding of cancer and potentially lead to new diagnostic reagents and therapies in the treatment of cancer.Read moreRead less
Regulation Of BRCA1 And APC Tumour Suppressor Functions By Nuclear Export
Funder
National Health and Medical Research Council
Funding Amount
$433,500.00
Summary
Cancer cells are unique, in that their ability to divide and grow is no longer controlled. Moreover, the DNA of cancer cells is less stable, and vital control genes often gain small mutations which culminate in a more aggressive or malignant cancer cell. Cancers from different tissues progress and respond in different ways to treatment, and the eventual development of tailored treatments or therapies will require a detailed understanding of how cancers from different tissues arise. Our laborator ....Cancer cells are unique, in that their ability to divide and grow is no longer controlled. Moreover, the DNA of cancer cells is less stable, and vital control genes often gain small mutations which culminate in a more aggressive or malignant cancer cell. Cancers from different tissues progress and respond in different ways to treatment, and the eventual development of tailored treatments or therapies will require a detailed understanding of how cancers from different tissues arise. Our laboratory studies two proteins, BRCA1 and APC, which are encoded by the genes most often associated with breast and colon cancer, respectively. We have made important discoveries linking the movement and location of these proteins inside the cell with their cancer-causing activity. In this project, we will continue to study how and why APC and BRCA1 move between different compartments inside cancer cells, and how this movement can sometimes signal cancer cells to die. Detailed understanding of these processes is essential for the eventual design of drug, peptide or gene therapies aimed at correcting defects in the expression or localisation of APC or BRCA1 in breast or colon cancer cells, and hopefully provide clues for that magic bullet that specifically targets and kills cancer cells.Read moreRead less
Regulation Of The Tumour Suppressors APC And BRCA1 By Nuclear Export
Funder
National Health and Medical Research Council
Funding Amount
$530,874.00
Summary
Cancer cells lack the ability to control their own growth, and thus continously divide in their local environment, leading to tumour formation. Tumour suppressor proteins, like APC and BRCA1, normally function as regulators to help cells respond to outside signals and to stop growing when necessary. The inactivation and altered cellular localisation of tumour suppressor proteins can contribute to cancer development. We have found that the APC and BRCA1 proteins, whose inactivation leads to devel ....Cancer cells lack the ability to control their own growth, and thus continously divide in their local environment, leading to tumour formation. Tumour suppressor proteins, like APC and BRCA1, normally function as regulators to help cells respond to outside signals and to stop growing when necessary. The inactivation and altered cellular localisation of tumour suppressor proteins can contribute to cancer development. We have found that the APC and BRCA1 proteins, whose inactivation leads to development of colon cancer and breast cancer, respectively, contain signals that dictate their movement within the cell. Our novel preliminary findings reveal that APC and BRCA1 are able to move in and out of the cell nucleus. We aim to define how this occurs, and examine how the regulation of their cellular location affects the normal function of these cancer-suppressing proteins. Finally, abnormalities in the nuclear passage of APC or BRCA1 might explain their altered cellular location in cancer cells.Read moreRead less
The focus of my research is mechanisms of growth factor receptor signal transduction and how they are altered in specific disease states, particularly cancer.
Tumor Specific Variants Of The EGFR: Characterization, Function And Target For Immunotherapy.
Funder
National Health and Medical Research Council
Funding Amount
$140,880.00
Summary
Antibodies are a major component of the bodies immune system that bind (i.e. stick) to foreign substances such as viruses. Once bound, these antibodies can activate other parts of the immune system, which help destroy the foreign substance. Analogous to the situation above, a number of institutions are testing antibodies that bind to cancer cells, in order to determine if they are able to destroy these cells. This therapeutic approach requires an antibody that specifically binds to cancer cells ....Antibodies are a major component of the bodies immune system that bind (i.e. stick) to foreign substances such as viruses. Once bound, these antibodies can activate other parts of the immune system, which help destroy the foreign substance. Analogous to the situation above, a number of institutions are testing antibodies that bind to cancer cells, in order to determine if they are able to destroy these cells. This therapeutic approach requires an antibody that specifically binds to cancer cells but not normal cells. In this proposal, we wish to test a novel antibody that binds to a protein on the cell surface called the EGF receptor. While the EGF receptor is found on the surface on many cells, our antibody recognizes a modified version of the EGF receptor that is found exclusively on cancer cells. Previous EGF receptor antibodies tested in the clinic all recognized the normal EGF receptor and thus proved unsuitable as they bound to cells in the liver causing significant side effects. It is anticipated that the specificity of our novel antibodies will overcome this problem. Eventually this antibody could be used to treat patients with brain, breast, prostate and lung cancer. We will also conduct a number of studies to determine the function of this modified receptor. This work will improve our understanding of those events associated with development of tumors.Read moreRead less
Tumour cells are often characterized by defects in signaling pathways. One of the most important signaling cascades involved in the development of cancer is the EGFR-Ras-MAPK pathway. EGFR is often overexpressed in breast cancer, leading to enhanced Ras signaling (hyperactive Ras) and cell transformation. The proposed project aims to identify the molecular mechanisms that can downregulate hyperactive Ras and will make a valuable contribution to our understanding of EGFR-Ras related cancers.