Identification And Characterization Of Substrates Of Tyrosine Kinases Involved In Hematopoiesis And Leukemia
Funder
National Health and Medical Research Council
Funding Amount
$241,527.00
Summary
The development and maintenance of tissues in mammals are tightly controlled and complex processes involving the growth, maturation and survival of vast numbers of cells of various types. In cancer, the cell's capacity to faithfully regulate these processes is diminished or lost. Many of the proteins that are essential for growth control are produced by an important class of genes called proto-oncogenes; literally, the prototypes of cancer-causing genes. Naturally occurring mutations in these ge ....The development and maintenance of tissues in mammals are tightly controlled and complex processes involving the growth, maturation and survival of vast numbers of cells of various types. In cancer, the cell's capacity to faithfully regulate these processes is diminished or lost. Many of the proteins that are essential for growth control are produced by an important class of genes called proto-oncogenes; literally, the prototypes of cancer-causing genes. Naturally occurring mutations in these genes have been identified in man and are likely to play a major role in the initiation and progression of distinct human malignancies. A significant number of proto-oncogenes are enzymes called protein tyrosine kinases (PTKs). Research has shown that the function of PTKs is to relay growth signals or other regulatory signals from the outer surface of the cell to specific target proteins inside the cell. These target proteins are needed to relay the signal to other target molecules and so on. This highly ordered process, involving a specific sequence of proteins, ensures that cells respond appropriately to a given signal. Our research focuses on identifying and studying the immediate targets of PTKs with the broad aim of understanding how PTKs control growth in normal and cancerous cells. We have recently developed a method that has enabled us to identify a new protein that may regulate the growth of blood cells. The research proposed here aims to extend our preliminary observations showing that the growth of specific types of blood cells is inhibited by this protein. We also plan to search for new targets of a PTK that is involved in leukemia. The findings of this research will provide important insight into how blood cells are regulated in health and disease.Read moreRead less
Structural Studies Of The Jak And Abl Kinases: A Prerequisite For Drug Design
Funder
National Health and Medical Research Council
Funding Amount
$360,965.00
Summary
Protein tyrosine kinases (PTK) are a large, pivotal family of signalling molecules implicated in diseases such as cancer and immune related disorders. This fellowship aims to develop more potent kinase inhibitors of a number of PTKs using Cytopia’s drug discovery capability coupled with the X-ray crystallography expertise within Monash University. This innovative approach will permit a rational structure-based drug discovery platform to be established and will lead to the creation of a portfolio ....Protein tyrosine kinases (PTK) are a large, pivotal family of signalling molecules implicated in diseases such as cancer and immune related disorders. This fellowship aims to develop more potent kinase inhibitors of a number of PTKs using Cytopia’s drug discovery capability coupled with the X-ray crystallography expertise within Monash University. This innovative approach will permit a rational structure-based drug discovery platform to be established and will lead to the creation of a portfolio of phase I therapeutics, which will be of substantial benefit in the medical health area.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.
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.
Structural Basis Of Ligand Binding To Type 1 Insulin-like Growth Factor Receptor (IGF-1R)
Funder
National Health and Medical Research Council
Funding Amount
$446,562.00
Summary
Insulin-like growth factors are involved in normal growth and development. However, they are also implicated in cancer development and progression. We are seeking to understand the way in which these growth factors bind to their receptor on the surface of the cell and stimulate the cell to survive, proliferate and migrate to new tumour sites. Such knowledge will be useful in the design of molecules that could potentially intervere with this process and thus be used as anti-cancer therapeutics.
Understanding The Role Of Tec In Fcgamma Receptor Mediated Phagocytosis
Funder
National Health and Medical Research Council
Funding Amount
$211,527.00
Summary
The recognition and destruction of bacterial pathogens and other foreign particles by specific immune cells (macrophages) is principally mediated by the Fcgamma class of cell surface antibody receptors. This proposal aims to understand the molecular mechanisms which link receptor activation to the cellular rearrangements required to invaginate or swallow the offending particle. We have used immunofluorescent microscopy and biochemical methods to show that the intracellular tyrosine kinase Tec is ....The recognition and destruction of bacterial pathogens and other foreign particles by specific immune cells (macrophages) is principally mediated by the Fcgamma class of cell surface antibody receptors. This proposal aims to understand the molecular mechanisms which link receptor activation to the cellular rearrangements required to invaginate or swallow the offending particle. We have used immunofluorescent microscopy and biochemical methods to show that the intracellular tyrosine kinase Tec is an important component of the phagocytosis mechanism. Here we plan to use highly selective gene targeting methods to generate a mouse cell culture model system which is devoid of Tec protein. This will allow us to determine whether Tec is essential for Fcgamma-mediated phagocytosis. Reintroduction of mutant versions of the Tec protein into this null background will provide detailed information on the molecular partners of Tec and the individual roles of the various domains within the Tec protein. By studying the molecular mechanism of phagocytosis, we expect to gain an understanding of how to influence the Fcgamma signalling pathway, either to enhance the ability to deal with pathogens, or to restrict the consequences of excessive phagocytosis associated with autoimmune diseases. Tec is an enzyme likely to play an important role between the Fcgamma receptor and actin cytoskeleton rearrangements and therefore is a potentially important drug target.Read moreRead less
C-Kit Signalling And Cellular Responses In Haemopoietic Cells
Funder
National Health and Medical Research Council
Funding Amount
$731,115.00
Summary
Growth factors acting on cell surface receptors activate multiple intracellular signalling pathways that regulate cellular growth and function. Mutations in the genes that code for these receptors or their downstream signalling pathways contribute to many human cancers. The contributions of different signalling pathways linked to these receptors to the various cellular responses (growth, maturation, functional activation) are not understood. In this project we aim to use cell and molecular biolo ....Growth factors acting on cell surface receptors activate multiple intracellular signalling pathways that regulate cellular growth and function. Mutations in the genes that code for these receptors or their downstream signalling pathways contribute to many human cancers. The contributions of different signalling pathways linked to these receptors to the various cellular responses (growth, maturation, functional activation) are not understood. In this project we aim to use cell and molecular biology approaches to determine the role of different signalling pathways in cellular responses mediated by the growth factor receptor c-Kit. The c-Kit receptor has essential functions in blood cell development, skin and hair pigmentation, gut function and the reproductive system. It is also essential for the development and function of mast cells which trigger allergic responses such as asthma and eczema. Mutant forms of the receptor have been identified in certain leukaemias and colon cancers. Many new drugs that target specific intracellular signalling pathways have recently been developed and are beginning to be evaluated in clinical trials. Better understanding of how individual pathways contribute to the function of c-Kit and other receptors is essential for optimal use of these new drugs. For example, it may enable the choice of drugs to block c-Kit dependent cancer cell growth or allergic reactions without affecting the growth of normal blood cells.Read moreRead less