We seek to gain a detailed understanding of how interactions between the West Nile virus proteins and host factors involved in the IFN response determine the outcome of virus infection. Better understanding of the mechanisms employed by this highly pathogenic virus to disable the mammalian host's IFN response will have wider implications for our understanding of other human diseases such as cancer, autoimmunity and provide new avenues for design of efficient antiviral and anticancer therapies.
Identifying Long-range Regulatory Elements Of The Breast Cancer Susceptibility Gene, BRCA1
Funder
National Health and Medical Research Council
Funding Amount
$612,842.00
Summary
BRCA1 is a breast cancer susceptibility gene implicated in both familial and sporadic breast cancers. The mechanisms controlling BRCA1 expression are poorly understood. We will identify DNA sequences critical for regulation of the BRCA1 gene. We hypothesise that these regions are mutational hot spots conferring an increased breast cancer risk. A better understanding of the pathways responsible for promoting BRCA1-associated breast cancer will provide important diagnostic and treatment targets.
Several members of the Flaviviridae family are major pathogens of humans including dengue (DEN), yellow fever (YF), tick-borne encephalitis (TBE), Murray valley encephalitis (MVE), Japanese encephalitis (JE), and hepatitis C virus (HCV). An Australian flavivirus Kunjin (KUN), however, appears to be naturally attenuated and does not cause an overt disease in humans. In contrast, genetically and antigenically closely related to KUN, New York strain of West Nile virus (NY WN) has already caused ~50 ....Several members of the Flaviviridae family are major pathogens of humans including dengue (DEN), yellow fever (YF), tick-borne encephalitis (TBE), Murray valley encephalitis (MVE), Japanese encephalitis (JE), and hepatitis C virus (HCV). An Australian flavivirus Kunjin (KUN), however, appears to be naturally attenuated and does not cause an overt disease in humans. In contrast, genetically and antigenically closely related to KUN, New York strain of West Nile virus (NY WN) has already caused ~500 deaths and over 20,000 registered infections since its emergence in North America in 1999, including 223 deaths and 9122 infections in 2003 alone. Recent studies with DEN indicated that flaviviruses may interfere with early steps of IFN-signalling pathway. The type I Interferon (IFN) response is the first line of defence against viral infections and many viruses have developed different strategies to counteract this response in order to ensure their survival in the infected host. In this grant we seek to exploit our extensive understanding of the molecular biology of KUN virus and the contrasting behaviour of KUN and NY WN viruses to gain an understanding of the role of flavivirus-mediated suppression of host anti-viral IFN response in virus-host relationships and its importance in determining virus virulence.Read moreRead less
Antibody-mediated Dendritic Cell Depletion To Attenuate GVHD
Funder
National Health and Medical Research Council
Funding Amount
$434,510.00
Summary
Not all patients with leukemia will be cured by chemotherapy. Stem cell transplantation improves their chances of survival. Stem cell transplantation requires intensive chemotherapy and radiotherapy to eradicate the underlying disease and infusion of healthy stem cells to provide an anti-leukemic effect and normal blood cells. Recovery from transplantation is not straightforward. Recovery can be hampered by the immunological reaction of the donor cells against the patient (Graft versus Host Dise ....Not all patients with leukemia will be cured by chemotherapy. Stem cell transplantation improves their chances of survival. Stem cell transplantation requires intensive chemotherapy and radiotherapy to eradicate the underlying disease and infusion of healthy stem cells to provide an anti-leukemic effect and normal blood cells. Recovery from transplantation is not straightforward. Recovery can be hampered by the immunological reaction of the donor cells against the patient (Graft versus Host Disease [GVHD]), despite immunosuppression. GVHD produces serious damage to the internal organs and lining of the mouth and gut. Recovery can also be circumvented by leukemic relapse. GVHD is associated with an increased risk of death and dying after transplantation. To date therapy for GVHD has relied on eliminating the T cells that cause the disease. However for T cells to cause damage they must first be primed with antigen presented on activated dendritic cells. The intensive conditioning therapy required to eradicate the underlying disease before transplantation also activates dendritic cells. Our project seeks to investigate the effects of lethal and non-lethal conditioning on dendritic cells with the aim of validating the use of antibodies designed to deplete activated dendritic cells as therapy for graft versus host disease.Read moreRead less
Macrophage Lineage Contribution To Breast Cancer Metastasis
Funder
National Health and Medical Research Council
Funding Amount
$602,501.00
Summary
When diagnosed early, breast cancer can be treated with a high degree of success. However, if the cancer spreads to other organs such as lungs and bone, patients suffer from severe pain and debilitating symptoms that often lead to death. Therapies for patients with advanced disease are extremely limited. It is the aim of this project to define the role that macrophages and stromal fibroblasts play in assisting the tumour cells to spread around the body and grow in other tissues.