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Altering Macrophage Phenotype For The Treatment Of Chronic Airway Disease And Lung Cancer
Funder
National Health and Medical Research Council
Funding Amount
$904,556.00
Summary
The aim of this proposal is to identify mechanisms through which the Src family kinase Hck promotes innate immune cell-dependent, chronic lung inflammation and lung cancer development. Our preliminary data suggest that excessive Hck activity provides a molecular mechanism to skew macrophage polarization towards an alternatively activated, M2-like phenotype associated with chronic airways disease, and the tumour promoting microenvironment.
A New Function For An Old Enzyme: Src Protein Kinase Directs Excitotoxic Neuronal Death In Stroke
Funder
National Health and Medical Research Council
Funding Amount
$513,975.00
Summary
In our previous investigation of how brain cells die in patients suffering from stroke, we found that stroke causes aberrant activation of an enzyme called Src in the affected brain cells. Furthermore, this aberrantly activated Src directs the brain cells to undergo cell death. Our proposal, which aims to decipher this neurotoxic mechanism of the aberrantly activated Src will benefit development of new therapeutic strategies to reduce brain damage in stroke patients.
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
Tumour Suppressor Networks: The Role Of SHIP-1 And Lyn In Suppressing Haematopoietic Tumours
Funder
National Health and Medical Research Council
Funding Amount
$469,526.00
Summary
Haematopoietic malignancies kill a large number of Australians each year. Improving our understanding of the molecular mechanisms that underlie these diseases is essential for the design of more effective treatments. Lyn and SHIP-1 are enzymes that are found in blood cells, and both participate in terminating cellular responses. As such, these enzymes are critically important for maintaining stability in the immune system. While these enzymes have unique roles, we also have good evidence that in ....Haematopoietic malignancies kill a large number of Australians each year. Improving our understanding of the molecular mechanisms that underlie these diseases is essential for the design of more effective treatments. Lyn and SHIP-1 are enzymes that are found in blood cells, and both participate in terminating cellular responses. As such, these enzymes are critically important for maintaining stability in the immune system. While these enzymes have unique roles, we also have good evidence that in some instances Lyn and SHIP-1 participate in the same biochemical pathway. We have created mice that are unable to make Lyn protein, and have found that these mice develop blood cell tumours. Mice lacking SHIP-1 develop a number of haematological defects, but die at a young age due to an inflammatory lung condition, making an assessment of the role of SHIP-1 in age-dependent tumour development difficult. We now wish to study the role of SHIP-1 in tumour development, by generating mice that lack SHIP-1 in specific white blood cell compartments. We are also investigating how SHIP-1 and Lyn cooperate in tumour suppression, and we have recently generated mice that simultaneously lack both SHIP-1 and Lyn. Preliminary studies indicate that compound mutant mice develop multiple haematological malignancies. We will fully characterize tumour development in these animals, and determine the molecular basis for this pathology. We will focus on two pathways that have been previously implicated in oncogenesis. These studies will improve our insight into how Lyn and SHIP-1 cooperate in blood cell development, cellular homeostasis and oncogenesis, and add to our biological and biochemical understanding of tumour suppressor networks.Read moreRead less
Regulation Of TNF And SFK Signalling In Immune Cells By TCPTP
Funder
National Health and Medical Research Council
Funding Amount
$454,023.00
Summary
Tumour necrosis factor (TNF) is a potent proinflammatory cytokine that plays an important role in immunity and inflammation. TNF acts on the cell surface to activate two key cellular communication or signalling pathways: the mitogen-activated protein kinase (MAPK) pathway and the nuclear factor kappaB (NFkappaB) pathway. The relative activation of the two pathways can dictate whether cells live and proliferate or differentiate or otherwise die in response to TNF, and therefore determine the natu ....Tumour necrosis factor (TNF) is a potent proinflammatory cytokine that plays an important role in immunity and inflammation. TNF acts on the cell surface to activate two key cellular communication or signalling pathways: the mitogen-activated protein kinase (MAPK) pathway and the nuclear factor kappaB (NFkappaB) pathway. The relative activation of the two pathways can dictate whether cells live and proliferate or differentiate or otherwise die in response to TNF, and therefore determine the nature of the immune or inflammatory response. The T-cell protein tyrosine phosphatase (TCPTP) is known to be important in the immune system and serves as a negative regulator of inflammation. Our preliminary studies have identified TCPTP as a selective regulator of TNF-induced MAPK but not NFkappaB signaling. TCPTP exerts its effects by inactivating Src family kinases (SFK) which are themselves integral to immune and inflammatory responses. In this proposal we will elucidate the molecular basis for TCPTP function in TNF- signalling and characterise the role of TCPTP in TNF and SFK functions in immune cells, in particular T-cells.Read moreRead less
Targeting TRPV4 Activation Mechanisms To Reveal Novel Pain Therapies
Funder
National Health and Medical Research Council
Funding Amount
$580,938.00
Summary
Pain nerves sense painful chemical and physical stimuli, by opening protein "ion channels" which let small electric currents traverse the cell membrane. This pain signal is transmitted to the spinal cord and then the brain, where it is perceived as pain and elicits a reaction. But we don't know how the ion channels open. This project will investigate how receptors for painful substances open ion channels to cause pain. Understanding this mechanism will help us to make new drugs to treat pain.
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
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.