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
Human Dendritic Cell Subsets And Their Application For Immunotherapy
Funder
National Health and Medical Research Council
Funding Amount
$443,946.00
Summary
Immunotherapy is a promising non-toxic strategy for the treatment of many cancers, viruses and other diseases. It works by teaching the patient's own immune system to recognize and destroy the cancer. Specialized blood cells called dendritic cells are essential to this process but they are poorly understood in humans. I aim to investigate the function these cells and use this information to develop new treatments for cancer and viruses.
In Vivo Imaging Of Protective And Malignant B Cell Function
Funder
National Health and Medical Research Council
Funding Amount
$431,412.00
Summary
B cells are responsible for producing antibody that protects us from infection. Disruption of healthy B cell function can lead to a myriad of diseases including immunodeficiency, autoimmunity and blood cancers such as leukaemia. The aim of my work is to use powerful microscopy to visualise how mutated B cells interact with their surrounding environment in real-time. These studies will allow the development of new treatments for cancer and immune conditions that target these interactions.
TARGETING THE HUMAN CROSS-PRIMING DENDRITIC CELLS FOR IMMUNOTHERAPY
Funder
National Health and Medical Research Council
Funding Amount
$589,544.00
Summary
Specialized white blood cells called dendritic cells (DCs) are essential to inducing the immune system to eradicate cancers and viral infections in mice. We have defined human DC subsets and related their functional capacities to the mouse DC subsets. We will now identify the human DC subsets involved in the induction of cancer and viral immune responses and use this information to develop clinical therapeutic cancer vaccination trials.
Investigating The Mechanism And Consequences Of Cytotoxic Lymphocyte Detachment
Funder
National Health and Medical Research Council
Funding Amount
$419,180.00
Summary
Killer cells are white blood cells that destroy cancerous cells. To move to their next target they must quickly detach from a dying target. Failure of detachment results in excessive inflammation and tumour escape. This project will discover the detachment signals required to ‘release’ a locked-on killer cell. This will lead to a deeper understanding of immune pathology and new ways of treating cancer.
Immune Imprinting By Nanoparticles And Vaccines: New Principles And Translation Into The Clinic
Funder
National Health and Medical Research Council
Funding Amount
$631,010.00
Summary
Vaccines require adjuvants to be effective. Despite decades of research there is only one adjuvant approved for broad use in humans. Based on our prior findings I will engage new principles in nanotechnology, and deepen understanding of immune imprinting in various organs of the body including the lung, to develop 2nd generation broadly useful nanoadjuvants able to effectively treat cancer and malaria.
NFkB1 Is A Novel Regulator Of CD8+ T Cell Development And Memory Cell Generation
Funder
National Health and Medical Research Council
Funding Amount
$438,039.00
Summary
This project is focused on understanding the role of a regulatory protein- NFkB1 and how it is capable of controlling the development of a class of white blood cells termed T cells. Using a mouse model, we reveal how the absence of NFkB1 is important for producing memory T cells. Studies are proposed to determine whether this is an novel way for generating long lived memory T cells against viral infections and cancer, and potentially a new strategy for vaccine development.