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
B Cell Survival And Responsiveness In Health And Disease
Funder
National Health and Medical Research Council
Funding Amount
$664,584.00
Summary
I am an immunologist focused on identifying how B lymphocytes, the cells responsible for producing antibodies, survive and participate in immune responses within the body. I achieve this by using specially designed, genetically modified, mice that allow me to follow B lymphocytes within the body and identify their key genetic and external controls. My work is relevant to vaccine development as well as the control of certain autoimmune diseases and B lymphocyte cancers.
Influence Of TCR Signals From Contact With Self-MHC Ligands On Naive T Cell Survival
Funder
National Health and Medical Research Council
Funding Amount
$418,658.00
Summary
A diverse repertoire of naive T cells constitutes a critical part of the adaptive immune system and protects hosts from various infections and cancer. T cells are stably maintained at a constant number in the periphery by mechanisms that are not clearly understood. This proposal will shed light on how the immune system preserves a diverse na�ve T cell pool able to respond against various foreign antigens, while preventing their harmful auto-reactivity to self antigens.
The Axis Of Bcl-2, Plasmacytoid DCs And Lupus As A Basis For Therapy
Funder
National Health and Medical Research Council
Funding Amount
$712,172.00
Summary
Systemic lupus erythematosus (SLE) affects 1 in 1000 Australians, mostly women. Here the immune system goes awry and makes antibodies against the body’s own components including the body’s DNA. This leads to damage to many parts of the body including kidneys, joints, brain and heart. It is incurable. A particular immune cell controls the development of this disease and we have found this cell is selectively killed by an inexpensive drug, which we hope will be a better way of treating SLE.
CCR9 Expressing T Helper Cells In Immunity And Autoimmunity
Funder
National Health and Medical Research Council
Funding Amount
$729,571.00
Summary
We have identified a unique subset of immune cells in autoimmune lesions named Tccr9 cells. You find these cells in the gut, but when the body shifts into disease mode, Tccr9 cells disseminate to the accessory organs of the digestive system. Understanding the relationship between gut Tccr9 cells and the Tccr9 cells that contribute to chronic inflammation and autoimmunity is the focus of this research proposal.
Understanding Pathogenicity And Immunity In An Encephalitic Mouse Model Of Hendra Virus Infection
Funder
National Health and Medical Research Council
Funding Amount
$572,342.00
Summary
Our understanding of Hendra virus infection and immunity is extremely limited and has been hampered by a lack of appropriate animal models of disease and reagents. This Project will employ a newly-established mouse model to study encephalitis, the most life-threatening manifestation of this infection. We will use unique, state-of-the-art infrastructure and a plethora of mouse-specific reagents to investigate the mechanisms involved in regulating the host response to infection.
Delineating Aberrant Adaptive Immune Responses Due To Germline Mutations In The PI3K Signalling Pathway
Funder
National Health and Medical Research Council
Funding Amount
$975,476.00
Summary
Activation of immune cells is required to generate appropriate immune responses that protect is from disease caused by pathogens. The inability to receive the correct type of signals causes immunodeficiency. The PI3 kinase pathway is central to immune cell activation – and genetic errors in this pathwat compromise the functioning of immune cells. We will investigate the nature of these defects and pursue avenues of overcoming them using pharmacological inhibitors of the PI3K pathway.
Our research has identified unprecedented communications between the microbes that colonize our body’s surfaces and killer T cell immunity. Our findings indicate that microflora is key to a healthy balance between two immune mediator systems that have opposing effect on T cell immunity. The project will extend our understanding of how this regulated and seeks to harness these novel insights to explain the well known, but poorly understood role of microbes in autoimmune diseases.