Investigation Of Cellular Abnormalities And Synapse Formation In DOCK8 Immunodeficiency
Funder
National Health and Medical Research Council
Funding Amount
$318,284.00
Summary
Why do some people get allergies? Or serious infections? To investigate this we will study mice and humans with a mutation in the DOCK8 gene. People with mutations in the DOCK8 gene get Hyper-IgE Syndrome and develop severe viral infections of the skin as well as allergic disease. By investigating how DOCK8 works in the cells of the immune system, we hope to understand why these infections and allergies occur and find out why these problems can also happen in those without this specific genetic ....Why do some people get allergies? Or serious infections? To investigate this we will study mice and humans with a mutation in the DOCK8 gene. People with mutations in the DOCK8 gene get Hyper-IgE Syndrome and develop severe viral infections of the skin as well as allergic disease. By investigating how DOCK8 works in the cells of the immune system, we hope to understand why these infections and allergies occur and find out why these problems can also happen in those without this specific genetic defect.Read moreRead less
Role Of PLZF In Regulating The Interferon Response
Funder
National Health and Medical Research Council
Funding Amount
$531,696.00
Summary
The Interferon (IFN) pathway is essential for immune defense against pathogens in vertebrates. IFNs both protect and alert cells about viral, bacterial, and other immune assaults and promote a cellular antiviral state, reduce proliferation, or induce apoptosis depending on the cell type and environment. Based on these properties, IFNs have been used clinically against a variety of diseases including viral infections, immunomodulatory disorders and hematologic and solid tumors including renal cel ....The Interferon (IFN) pathway is essential for immune defense against pathogens in vertebrates. IFNs both protect and alert cells about viral, bacterial, and other immune assaults and promote a cellular antiviral state, reduce proliferation, or induce apoptosis depending on the cell type and environment. Based on these properties, IFNs have been used clinically against a variety of diseases including viral infections, immunomodulatory disorders and hematologic and solid tumors including renal cell carcinoma. However, the factors determining outcome of IFN treatment, remain to be determined. We have identified a subset of interferon stimulated genes whose sustained expression was found to correlate with heightened antiviral sensitivity of renal cell carcinoma cell lines to IFN. Many of these genes were found to have binding sites for the transcriptional repressor promyleocytic zinc finger protein (PLZF). PLZF was first identified in a subset of Acute Promyelocytic Leukemia patients and is involved in maintenance of erythroid lineage stem cells and spermatogonial stem cells in male mice. PLZF has not previously been implicated in the IFN response. Accordingly, we investigated the expression of interferon stimulated genes and showed that increased expression of immune related genes depends on PLZF expression. PLZF was also found to directly associate with binding sites in promoters of interferon stimulated genes and that this requires histone deacetylation. Thus, we uncovered a novel function for PLZF in enhancement of IFN associated gene expression. We propose to test the hypothesis that PLZF is an essential component of the IFN response. As a corollary, we will also test whether PLZF expression can be linked to IFN responsiveness in renal cell carcinoma. These studies will establish the role of PLZF in the IFN response and define its utility in predicting IFN responsiveness in therapeutic applications.Read moreRead less
Role For Sphingosine Kinase-1 In Endothelial Progenitor Cell Survival And Differentiation.
Funder
National Health and Medical Research Council
Funding Amount
$294,205.00
Summary
Lay description: Collectively, diseases of the vascular system contribute immensely to the burden of health care in Australia. Notably, abnormal blood vessel formation and function (angiogenesis) has been identified as a major cause or contributor to the vascular complications associated with inflammation, cancer, rheumatoid arthritis and diabetes. Endothelial cells are one of the principle cells of blood vessels forming a barrier between the blood and tissues. This project aims to understand th ....Lay description: Collectively, diseases of the vascular system contribute immensely to the burden of health care in Australia. Notably, abnormal blood vessel formation and function (angiogenesis) has been identified as a major cause or contributor to the vascular complications associated with inflammation, cancer, rheumatoid arthritis and diabetes. Endothelial cells are one of the principle cells of blood vessels forming a barrier between the blood and tissues. This project aims to understand the process whereby mature endothelial cells are formed and how replacement of damaged endothelial cells is normally achieved. Stem cell therapy is considered the new frontier for the treatment of many diseases. Understanding how endothelial progenitor cells differentiate to mature endothelial cells and the signals which operate inside the cell may allow therapeutic manipulation of key target moecules in order to limit or control inflammation, tumourigenesis, rheumatoid arthritis and diabetic retinopathy. Our results suggest that one target maybe the enzyme sphingosine kinase.Read moreRead less
Understanding The Role Of Innate Immune Cells In Regulating Gut-associated Lymphoid Tissues At Steady-state And In Disease
Funder
National Health and Medical Research Council
Funding Amount
$365,126.00
Summary
The intestine is the largest surface area forming a protective barrier between the external environment and the body. It represents the first line of defence against invading pathogens. The immune system of the intestine is critical to protect this tissue -any breakdown leads to profound and progressive inflammatory disease of the gut such as chronic inflammatory bowel disease. Our work will determine the critical the mechanisms that protect the gut opening the door to targeted intestinal immuno ....The intestine is the largest surface area forming a protective barrier between the external environment and the body. It represents the first line of defence against invading pathogens. The immune system of the intestine is critical to protect this tissue -any breakdown leads to profound and progressive inflammatory disease of the gut such as chronic inflammatory bowel disease. Our work will determine the critical the mechanisms that protect the gut opening the door to targeted intestinal immunotherapeutics.Read moreRead less