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Studies On The Flavivirus Nonstructural Proteins And Untranslated Regions Of The Genome Involved In Virus Replication
Funder
National Health and Medical Research Council
Funding Amount
$244,277.00
Summary
Flaviviruses cause potentially fatal diseases of global importance such as yellow fever, Japanese encephalitis (JE) and dengue haemorrhagic fever. Flavivirus disease is also important in Australia with recurrent outbreaks of dengue fever, Australian encephalitis and more recently JE in the northern regions of the continent. Effective vaccines are only available to yellow fever and JE and tick-borne encephalitis and are either live or killed preparations which are potentially hazardous and costly ....Flaviviruses cause potentially fatal diseases of global importance such as yellow fever, Japanese encephalitis (JE) and dengue haemorrhagic fever. Flavivirus disease is also important in Australia with recurrent outbreaks of dengue fever, Australian encephalitis and more recently JE in the northern regions of the continent. Effective vaccines are only available to yellow fever and JE and tick-borne encephalitis and are either live or killed preparations which are potentially hazardous and costly to produce. There are no therapeutic agents (antivirals) available against flavivirus diseases. To produce safe and cost effective vaccines against flaviviruses and to identify targets for antiviral agents, a more complete understanding of how these viruses replicate in the cell and cause disease is required. This investigation aims to define specific aspects of the flavivirus life cycle that are currently unknown.Read moreRead less
MOLECULAR STRUCTURE-FUNCTION RELATIONSHIPS OF THE NORADRENALINE TRANSPORTER & DRUG ACTION
Funder
National Health and Medical Research Council
Funding Amount
$188,912.00
Summary
The transmission of impulses by nerves is dependent on the release of chemicals, termed neurotransmitters, from the nerve. The neurotransmitter causes its effects and then its action is usually terminated by membrane proteins that transport the chemical back into the nerve. These proteins are termed 'transporters'. In the brain, psychostimulants such as cocaine and also drugs that are used in the therapy of conditions such as depression block the activity of the transporters for the neurotransmi ....The transmission of impulses by nerves is dependent on the release of chemicals, termed neurotransmitters, from the nerve. The neurotransmitter causes its effects and then its action is usually terminated by membrane proteins that transport the chemical back into the nerve. These proteins are termed 'transporters'. In the brain, psychostimulants such as cocaine and also drugs that are used in the therapy of conditions such as depression block the activity of the transporters for the neurotransmitters, noradrenaline, serotonin and dopamine. Recently, the structures of the transporter proteins have been determined using molecular biology techniques. The focus of this project is to determine the parts of the noradrenaline transporter protein structure that are important in determining its functions, utilising the knowledge that we now have about its molecular structure. This will lead to exciting advances in understanding the function of the noradrenaline transporter and these advances should ultimately lead to the development of more effective antidepressant drugs and of drugs to prevent the effects of psychostimulants such as cocaine.Read moreRead less
Control of transcription by the cardiac homeodomain protein Nkx2-5. The transcriptional regulatory protein Nkx2-5, a member of the homeodomain superfamily, is essential for heart development and mutations in the human gene cause congenital heart disease. We seek to define the molecular mechanisms that regulate the transcriptional activity of Nkx2-5. We have previously identified a transcriptional activation domain in the C-terminal region that is bipartite in nature and conserved among Nkx2-5 ....Control of transcription by the cardiac homeodomain protein Nkx2-5. The transcriptional regulatory protein Nkx2-5, a member of the homeodomain superfamily, is essential for heart development and mutations in the human gene cause congenital heart disease. We seek to define the molecular mechanisms that regulate the transcriptional activity of Nkx2-5. We have previously identified a transcriptional activation domain in the C-terminal region that is bipartite in nature and conserved among Nkx2-5 proteins from diverse species. We will characterise the consequences of mutations in this domain in mouse models and search for interacting proteins. Results will advance our understanding of gene regulation in the context of heart disease.Read moreRead less
Subunit stoichiometry and arrangement in the glycine receptor. Glycine receptors are important for nervous system function. These receptors comprise a mixture of 5 alpha and beta subunits arranged around a central ion-conducting pore. The subunit stoichiometry (i.e., numbers of alpha and beta subunits) and arrangement (i.e., subunit order) are unknown. The first aim of this project is to define these parameters using tethered subunits. The second aim is to use the tethered subunits to probe th ....Subunit stoichiometry and arrangement in the glycine receptor. Glycine receptors are important for nervous system function. These receptors comprise a mixture of 5 alpha and beta subunits arranged around a central ion-conducting pore. The subunit stoichiometry (i.e., numbers of alpha and beta subunits) and arrangement (i.e., subunit order) are unknown. The first aim of this project is to define these parameters using tethered subunits. The second aim is to use the tethered subunits to probe the structure and function of glycine and zinc binding sites at an unprecedented level of resolution. The results will provide crucial new information concerning glycine receptor structure and function.Read moreRead less
QacA-mediated Multidrug Resistance And Export In Staphylococcus Aureus
Funder
National Health and Medical Research Council
Funding Amount
$437,545.00
Summary
Strains of the pathogenic bacterium Staphylococcus aureus (Golden Staph) which are resistant to almost all available anti-staphylococcal agents are responsible for serious infections among hospitalised patients; in some hospitals such outbreaks reach epidemic proportions. In these bacteria, resistance has emerged to all classes of antimicrobial agents, including antibiotics and antiseptics-disinfectants commonly used in the hospital environment, largely due to the acquisition of resistance deter ....Strains of the pathogenic bacterium Staphylococcus aureus (Golden Staph) which are resistant to almost all available anti-staphylococcal agents are responsible for serious infections among hospitalised patients; in some hospitals such outbreaks reach epidemic proportions. In these bacteria, resistance has emerged to all classes of antimicrobial agents, including antibiotics and antiseptics-disinfectants commonly used in the hospital environment, largely due to the acquisition of resistance determinants. These determinants encode for proteins which provide the bacterial cell with a range of different biochemical mechanisms to evade antibiotic chemotherapy. Specifically, this project seeks to increase our understanding of proteins which confer resistance by pumping a variety of structurally-dissimilar antimicrobials out of the bacterial cell. Proteins which recognise such a broad spectrum of compounds are called multidrug resistance proteins and present a disturbing clinical threat since the acquisition of one such system by a cell may simultaneously decrease its susceptibility to a number of antimicrobials. Similar multidrug pumps are widespread in nature and are credited for resistance to antibiotics and other chemotherapeutic drugs in many pathogenic organisms, such as the bacteria responsible for tuberculosis, and in human cancer cells. In this project, we aim to characterise the QacA multidrug resistance protein which is involved in pumping many different antimicrobial compounds from staphylococcal cells. We will identify the regions of the QacA multidrug resistance protein which bind the compounds and examine how the protein expels them to give resistance. These studies are a prerequisite for the design of more effective antibacterial compounds able to bypass these drug resistance pumps, and will also provide fundamental knowledge applicable to the problem of multidrug resistance in other infectious diseases and cancer.Read moreRead less