Defining The Role And Contribution Of Cdc37 To Signal Transduction And Tumourigenesis By Src-family Kinases
Funder
National Health and Medical Research Council
Funding Amount
$411,430.00
Summary
Cells respond to extracellular stimuli, such as growth factors and hormones, by activating intracellular networks of signaling molecules. It is the activation of these signaling networks that is ultimately responsible for mediating the biological responses of cells to extracellular stimuli (e.g. insulin stimulating glucose metabolism by cells). Members of the Src-family of tyrosine kinases are paramount among signaling molecules, as they are able to directly initiate the activation of a cascade ....Cells respond to extracellular stimuli, such as growth factors and hormones, by activating intracellular networks of signaling molecules. It is the activation of these signaling networks that is ultimately responsible for mediating the biological responses of cells to extracellular stimuli (e.g. insulin stimulating glucose metabolism by cells). Members of the Src-family of tyrosine kinases are paramount among signaling molecules, as they are able to directly initiate the activation of a cascade of signaling networks that regulate the activity of the cell. Significantly though, the inappropriate activation of Src-family kinases has been implicated in the development of cancer, particularly breast and colon cancer, in humans. To fulfill their signaling functions however, Src-family kinases must first be folded into an active conformation upon their synthesis in the cell then be maintained in this conformation. Although previous studies, including our own, have implicated a class of proteins called molecular chaperones in this process, little is known about how the folding of Src-family kinases by these proteins is achieved and regulated. The overall aim of this study is to determine how the folding of Hck, one member of the Src-family of tyrosine kinases, into a conformation that enables it to participate in signaling networks is achieved and regulated. It is expected that the results from this study will provide significant new insight into how this process might influence the ability of cells to respond to extracellular stimuli and potentially contribute to the conversion of a normal cell into one with tumourigenic properties. Findings from this project may be particularly important in the context of human cancer. A better knowledge of how the signaling activity of Src-family kinases is regulated by molecular chaperones might provide a new avenue of investigation for the identification of novel chemotherapeutic agents.Read moreRead less
Genetic Approaches To Understand How Imbalanced Cytokine Signalling Drives The Pathogenesis Of Emphysema
Funder
National Health and Medical Research Council
Funding Amount
$519,715.00
Summary
Emphysema is a major component of Chronic Obstructive Pulmonary Disease (COPD), the fifth leading cause of death in Australia for which there is no effective treatment. We have discovered a specific mutation in a gene called gp130 that results in the formation of emphysema in mice. This finding allows us to understand the exact mechanisms by which this mutation causes emphysema, and therefore has the potential to uncover new strategies to design novel therapies against emphysema in humans.
Cross-talk Between Cytokine And Pathogen Recognition Receptor Networks In The Pathogenesis Of Gastric Cancer
Funder
National Health and Medical Research Council
Funding Amount
$174,800.00
Summary
Stomach cancer is the second most common cause of cancer-related deaths worldwide, and results in the yearly death of several thousand people in Australia alone. We have discovered a specific mutation in a gene called gp130 that results in the formation of gastritis and stomach cancer in mice. We are now aiming to understand the exact molecular events by which this mutation results in chronic inflammation and the subsequent uncontrolled growth of epithelial cells that line the stomach wall.
Mature red cells develop from hemopoietic stem cells in the adult bone marrow. The production of red blood cells is primarily controlled by the hormone erythropoietin (Epo). Previously we had identified that the protein Lyn must be present inside primitive red blood cells for Epo to stimulate them to become mature functional cells. We will determine the role of several molecules that interact with Lyn including Cbp, Liar and LACM, towards apects of red blood cell development.
Inhibition Of Nef-activated Src-family Kinases By CHK
Funder
National Health and Medical Research Council
Funding Amount
$514,307.00
Summary
HIV hijacks infected blood cells to produce its own proteins. Nef is one of these proteins and Nef alone is sufficient to cause an AIDS-like disease. Recently, we discovered that a protein called CHK can inhibit Nef. Our research will determine how CHK inhibits Nef and test the feasibility of drugs based on CHK. Such drugs would slow AIDS progression, assisting conventional therapies and patients' immune systems to combat the infection, leading to longer, healthier, more productive lives.
Roles Of Ndfip1 And Ndfip2 As Adaptors For The Nedd4 Family Of Ubiquitin Ligases
Funder
National Health and Medical Research Council
Funding Amount
$656,395.00
Summary
Part of this proposal is to understand how the body controls iron uptake through one of the iron transporters (DMT1). We will also study how proteins called Ndfip1 and Ndfip2 that regulate DMT1, also control other cellular processes, such as protection against brain damage following trauma. The results from this study should ultimately contribute to the development of therapies for certain human pathologies.
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