Epigenetic Regulation Of CD8+ T Cell Function And Memory.
Funder
National Health and Medical Research Council
Funding Amount
$578,171.00
Summary
Upon virus infection, a subset of white blood cells, called killer T cells, are recruited to fight the infection. This proposal aims to examine molecular changes that occur within killer T cells and impart their specific function. We also aim to understand how killer T cells are _programmed� as they establish immunological memory. This proposal will provide insights important for the design and improvement of vaccine strategies to fight pathogens such as influenza, HIV and even tumors.
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
Transcriptional Regulation And The Role Of Key Histone Variants In Defining Gene-specific Chromatin States.
Funder
National Health and Medical Research Council
Funding Amount
$450,696.00
Summary
One of the most outstanding and significant questions within this genome era has been to unravel how chromatin structure within the nucleus of a cell is capable of regulating the complex expression patterns needed for cell proliferation, cell differentiation and cellular responses to environmental factors such as pathogens and signaling molecules. Studies on lower eukaryotes have demonstrated that deposition of histone variants provides a powerful mechanism for modulating chromatin structure. To ....One of the most outstanding and significant questions within this genome era has been to unravel how chromatin structure within the nucleus of a cell is capable of regulating the complex expression patterns needed for cell proliferation, cell differentiation and cellular responses to environmental factors such as pathogens and signaling molecules. Studies on lower eukaryotes have demonstrated that deposition of histone variants provides a powerful mechanism for modulating chromatin structure. To date, there is no comprehensive picture of the contribution of histone variants in the transcriptional process in higher eukaryotes. Preliminary results obtained in our laboratory have provided fascinating first insights into the role of key histone variants in the control of regulatory regions of key genes involved in the immune system. Importantly, these results have enabled us to identify a novel chromatin regulatory mechanism that this proposal aims to investigate in necessary detail. The outcome of the proposed research will give an in depth understanding on how chromatin structure is influenced by the recruitment of histone variants and how this mechanism is crucially involved in gene regulation. Crucially, we will attempt to answer some of the most outstanding and significant questions about how chromatin dynamics within the nucleus switch on-off a defined subset of genes in response to a particular environmental stimulus. In addition, the new level of understanding of the events in metastasis-invasion will help provide advances in cancer and gene therapy.Read moreRead less
CD4 T-cell Deficiency And Dysfunction In HIV Patients Receiving Effective Antiretroviral Therapy
Funder
National Health and Medical Research Council
Funding Amount
$490,020.00
Summary
Large numbers of people throughout the world will commence antiretroviral treatment for HIV infection over the next 5 years. This treatment partially corrects CD4 T-cell deficiency (the most characteristic immune defect caused by HIV infection) but does not restore the immune system to normal in patients who were very immunodeficient before treatment. This study will determine the cause of residual immune defects in patients receiving antiretroviral drugs with the aim of introducing new therapie ....Large numbers of people throughout the world will commence antiretroviral treatment for HIV infection over the next 5 years. This treatment partially corrects CD4 T-cell deficiency (the most characteristic immune defect caused by HIV infection) but does not restore the immune system to normal in patients who were very immunodeficient before treatment. This study will determine the cause of residual immune defects in patients receiving antiretroviral drugs with the aim of introducing new therapies to correct those defects. Our previous studies have demonstrated that the production of new T-cells in HIV patients receiving antiretroviral durgs is affected by the function of the thymus, but that this does not account for the production of all new T-cells. We will investigate other sites of T-cell production in the body. We have also previously shown that poor recovery of CD4 T-cells in patients successfully treated with antiretroviral drugs is associated with immune activation and that the T-cells do not function adequately, even when CD4 T-cell counts are substantially increased. We will determine whether these abnormalities are the result of a persistent defect in T cell activation by monocytes and-or dendritic cells. The findings of our studies will improve the treatment and life-expectancy of individuals with HIV infection.Read moreRead less
Prof Carbone’s laboratory specialises in the study of immunity at the body surfaces. These surfaces include skin and mucosal tissues such as respiratory and gastrointestinal tract, all of which are the common points of entry for a variety of infectious agents. He has found that there exist cells at these peripheral sites that are separate from the immune components that one finds in the blood and, more importantly, that provide a profound level of protection during new infection. He now propose ....Prof Carbone’s laboratory specialises in the study of immunity at the body surfaces. These surfaces include skin and mucosal tissues such as respiratory and gastrointestinal tract, all of which are the common points of entry for a variety of infectious agents. He has found that there exist cells at these peripheral sites that are separate from the immune components that one finds in the blood and, more importantly, that provide a profound level of protection during new infection. He now propose to determine how best to induce this type of peripheral immune protection and how one can exploit these mechanisms for the purpose of infection control.Read moreRead less