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
Drugs are broken down in the body by the process of metabolism. Metabolism is important as both a detoxification and elimination mechanism, and determines dose rate for chronically administered drugs. Many drugs are metabolised by a reaction called glucuronidation. We will characterise the various components of the glucuronidation reaction in an integrated manner in order to understand and predict factors that influence an individual's capacity to metabolise drugs and other chemicals.
Understanding And Controlling PAS Domain Interactions In Basic Helix-loop-helix Transcription Factors
Funder
National Health and Medical Research Council
Funding Amount
$599,918.00
Summary
We want to understand how particular proteins control the activity of genes that are a crucial part of the body's ability to respond to environmental stresses, such as low oxygen, seizure and environmental pollutants. The knowledge gained will help decipher the events that result in correct function in the cell, and the misregulation that leads to toxic outcomes and disease states. We will search for new compounds with potential application as therapeutics for cancer, heart disease and stroke.
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.
Quantitative In Vitro-in Vivo Extrapolation: Realising The Promise
Funder
National Health and Medical Research Council
Funding Amount
$529,509.00
Summary
Most drugs are 'broken down', or metabolised, in the body by enzymes which are located mainly in liver. Knowing the efficiency of drug metabolism in patients is important for the discovery of new drugs and for the rational use of established drugs. This project will develop in vitro, or test-tube, approaches that predict how well a drug is metabolised in humans and whether it will interact with coadminsitered drugs. In turn, this allows prediction of drug dosage and frequency of administration.