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
Dissecting The Role Of The IL-3 Receptor Alpha Subunit And Beta-catenin In Acute Myeloid Leukaemia
Funder
National Health and Medical Research Council
Funding Amount
$583,312.00
Summary
Leukaemia is a devastating form of blood cancer affecting both young and old. We aim to understand the mechanisms of uncontrolled cell growth associated with acute myeloid leukaemia. We focus on the role of key growth regulators that are abnormally active in the critical leukaemia stem cells. Understanding the biological and molecular properties of these cells is of considerable importance for development of the next generation of leukaemia therapies.
T cells play a central role in the immune response. The primary event in T cell activation is the triggering of a specific T cell receptor (TCR). Our studies will examine whether the protein TCPTP antagonises TCR-instigated T cell responses. Our studies may provide important new insights into alternative approaches for manipulating T cell-mediated immune responses in diseased states.
Genetic Dissection Of The Function Of The Src Family Tyrosine Kinase Hck In Inflammatory Lung Disease
Funder
National Health and Medical Research Council
Funding Amount
$323,750.00
Summary
This project aims to identify better and safer treatments for serious, life-threatening inflammatory lung diseases, such as Chronic Obstructive Lung Disease (COPD), which affect over 600 million people worldwide and are a major health problem in Australia. There are no effective treatments that can reverse or slow these diseases. The research is based on our recent discovery that an enzyme called Hck might play a very important role in lung disease. We used mice in which a genetic method had bee ....This project aims to identify better and safer treatments for serious, life-threatening inflammatory lung diseases, such as Chronic Obstructive Lung Disease (COPD), which affect over 600 million people worldwide and are a major health problem in Australia. There are no effective treatments that can reverse or slow these diseases. The research is based on our recent discovery that an enzyme called Hck might play a very important role in lung disease. We used mice in which a genetic method had been used to change Hck into its active form. The mice appeared normal when they were born but developed a progressive lung inflammation that resembled serious human lung diseases. Surprisingly, the mice also displayed enhanced responses to substances from bacteria that can infect the lung - a so-called innate immune response. This led us to conclude that the main problem in the mice was actually enhanced innate immunity - which is usually protective - turning against the lung to cause disease. To understand exactly what controls this fine balance between protection and lung damage, we will use new and sophisticated gene modification methods that allow us to target changes in Hck activity to specific cells that we suspect are the main cause of the disease. In doing so we will add special tags into these cells, so that we can isolate the controlling molecules in the disease process. We are particularly interested in a cell called the macrophage, a major defensive cell in the lung that is also known to be capable of causing lung disease. Our aim is to find disease-controlling molecules that could be blocked with new drugs that would suppress disease but spare defenses against lung infections.Read moreRead less
Src Family Kinases: Regulation Of Phosphoinositol-3 Kinase Signaling And Autoimmune Disease Development.
Funder
National Health and Medical Research Council
Funding Amount
$526,683.00
Summary
The immune system has to be capable of responding to an unlimited array of pathogens, but at the same time remain unresponsive to, or tolerant of, self-antigens. A breakdown in the tolerance to self-antigens results in autoimmunity. Autoimmune disease includes more than 70 chronic disorders that affect about 1 in 20 people in the Western population. Improving our understanding of the mechanisms that underlie autoimmune disease is essential for the design of more successful treatments. The Lyn ty ....The immune system has to be capable of responding to an unlimited array of pathogens, but at the same time remain unresponsive to, or tolerant of, self-antigens. A breakdown in the tolerance to self-antigens results in autoimmunity. Autoimmune disease includes more than 70 chronic disorders that affect about 1 in 20 people in the Western population. Improving our understanding of the mechanisms that underlie autoimmune disease is essential for the design of more successful treatments. The Lyn tyrosine kinase is an enzyme that is found within blood cells. It participates in transmitting information across the cell membrane to turn off cellular responses. Studies in mutant mice have shown that Lyn is critically important for maintaining stability in the immune system. Mice that are unable to make Lyn protein (Lyn-deficient mice) as well as mice that express an activated form of the Lyn enzyme (Lyn-up mice) develop autoimmune disease with characteristics similar to the human autoimmune disease systemic erythematosus (SLE). These studies suggest that Lyn is an important severity gene in autoimmunity. The aim of this grant will be to identify Lyn-dependent signaling pathways that lead to autoimmune disease, with a major focus being on the lipid kinase pathway. We will use a combination of genetic and biochemical approaches to reveal critical genes and pathways. Cataloging the molecular changes related to alterations in Lyn activity will, we believe, provide insight into the genetic defects or signal perturbations underlying human autoimmune diseases. In this way, our study will aid in the diagnosis of human autoimmune diseases and uncover useful targets for more specific and effective treatments.Read moreRead less