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The Role Of Past Sun Exposure, Infection History And Other Exogenous Factors In Multiple Sclerosis
Funder
National Health and Medical Research Council
Funding Amount
$92,011.00
Summary
Multiple Sclerosis (MS) is a chronic autoimmune inflammatory disease of the brain and spinal cord that leads to various degrees of disability. The causes of MS are not yet known, and there is presently no cure. However, there is strong evidence that both an inherited susceptibility and environmental factors are important. This environmental case control study will be conducted in Tasmania and will run concurrent to a genetic project on MS which allows assessment of gene-environment interactions. ....Multiple Sclerosis (MS) is a chronic autoimmune inflammatory disease of the brain and spinal cord that leads to various degrees of disability. The causes of MS are not yet known, and there is presently no cure. However, there is strong evidence that both an inherited susceptibility and environmental factors are important. This environmental case control study will be conducted in Tasmania and will run concurrent to a genetic project on MS which allows assessment of gene-environment interactions. It focuses on infections, timing of childhood infections and long term sun exposure. It has been suggested that MS may be due to an immune disturbance following viral infection and that the timing of childhood infections may be initially important. Also, in Australia, there is a sevenfold increase in MS prevalence as one moves from Queensland to Tasmania. This latitudinal gradient might be due to ultra violet radiation, through an influence on immune function. Beside those main focuses, the study will include other environmental factors like chemicals, diet and vaccinations. Hopefully this project will contribute to a better understanding of the causes of MS, which are relevant for preventative strategies and devising optimal treatment.Read moreRead less
Viral Factors Involved In Flavivirus Replication And Virus-host Interactions
Funder
National Health and Medical Research Council
Funding Amount
$743,696.00
Summary
With our increased understanding of virus-host interactions it has become apparent that small, non-structural proteins and small RNAs of most viruses are vital for numerous, often multiple, functions in the viral life cycle. In the proposed project, we seek to gain a detailed understanding of the functions of small nonstructural protein NS2A and small abundant viral RNAs of medicaly important encephalitic flaviviruses, which have remained so far elusive and are at the cutting-edge in the researc ....With our increased understanding of virus-host interactions it has become apparent that small, non-structural proteins and small RNAs of most viruses are vital for numerous, often multiple, functions in the viral life cycle. In the proposed project, we seek to gain a detailed understanding of the functions of small nonstructural protein NS2A and small abundant viral RNAs of medicaly important encephalitic flaviviruses, which have remained so far elusive and are at the cutting-edge in the research field. We anticipate that with a better understanding of the roles of these factors in flaviviral replication and pathogenesis, novel targets for antiviral therapies and-or molecular determinants for inclusion in candidate vaccines will be identified.Read moreRead less
SERPINB2 IS AN INDUCIBLE HOST FACTOR INVOLVED IN ENHANCING HIV-1 TRANSCRIPTION AND REPLICATION
Funder
National Health and Medical Research Council
Funding Amount
$496,446.00
Summary
SerpinB2 is one of the most abundant proteins made at sites of inflammation. We have shown that HIV-1 infection also induces SerpinB2 and that SerpinB2 then helps the virus to replicate. In this grant we seek to understand how the virus causes this protein to be made and how this protein then increases virus replication. In the human population there are different forms of SerpinB2 and this grant seeks to determine whether these different forms affect HIV-1 replications differently. It may for i ....SerpinB2 is one of the most abundant proteins made at sites of inflammation. We have shown that HIV-1 infection also induces SerpinB2 and that SerpinB2 then helps the virus to replicate. In this grant we seek to understand how the virus causes this protein to be made and how this protein then increases virus replication. In the human population there are different forms of SerpinB2 and this grant seeks to determine whether these different forms affect HIV-1 replications differently. It may for instance be possible that an individual who has a certain form of SerpinB2 may be less susceptable to AIDS following HIV-1 infection.Read moreRead less
Immunopathogenesis Of West Nile Virus Encephalitis - Requirement For Interferon-gamma-dependent Soluble Mediators
Funder
National Health and Medical Research Council
Funding Amount
$250,500.00
Summary
Flaviviruses transmitted by arthropods cause considerable illness and death world-wide by their propensity to cause encephalitis. In August 1999, an outbreak of West Nile virus (WNV) encephalitis occurred in New York for the first time, indicating that these viruses are spreading beyond endemic areas. However, the mechanisms by which these viruses kill people are not at all clear. How the immune system deals with them is controlled by a complex network of interactions involving cells and soluble ....Flaviviruses transmitted by arthropods cause considerable illness and death world-wide by their propensity to cause encephalitis. In August 1999, an outbreak of West Nile virus (WNV) encephalitis occurred in New York for the first time, indicating that these viruses are spreading beyond endemic areas. However, the mechanisms by which these viruses kill people are not at all clear. How the immune system deals with them is controlled by a complex network of interactions involving cells and soluble mediators such as cytokines, chemokines, and nitric oxide, many induced or modulated by the cytokine, inteferon-gamma. Evidence suggests that these agents together influence both the types of cells that are mobilised to eradicate virus and also disease outcomes. Our hypothesis is that the host's own immune system is inadvertently responsible for encephalitis through an over-vigorous attempt to destroy the infecting virus, resulting in damage to the brain. To study WNV encephalitis, we are using a mouse model developed in this laboratory that reproduces the features of human disease. Another strain of these mice has the gene for interferon-gamma (IFN) inactivated or 'knocked out', so they cannot respond in the conventional way to virus infection. This mouse survives WNV infection significantly better than normal mice and becomes immune. Therefore we will compare cellular and soluble mediator responses of these mice during WNV infection to those of normal mice. We will also delete specific cell types making interferon-gamma in normal mice, as well as transfering such cells into knockout mice. Experiments will indicate which cell types are responsible and when particular components cause most damage. Thus, we will better understand how interferon-gamma recruits cells that mediate immune brain damage in this model. By understanding the events that lead to death in encephalitis, it may be possible to prevent or ameliorate them by means of immune intervention.Read moreRead less
Statistical Methods For Identifying Structural Variation In Tumour Genomes Using Next Generation Sequencing
Funder
National Health and Medical Research Council
Funding Amount
$243,458.00
Summary
New DNA sequencing technology can sequence a tumour genome affordably in 2 weeks. This re-sequencing data can be used to find small mutations and large-scale chromosomal rearrangements that together are the drivers of cancer. These may one day be used to guide cancer therapy. This project will develop new algorithms for finding mutations and apply these to discover the genetic basis of drug resistance in a model lymphoma system.
Mortality In Young Offenders Who Have Had Custodial Sentences
Funder
National Health and Medical Research Council
Funding Amount
$60,448.00
Summary
The proposal seeks funding to investigate the death rate in young people who have received custodial sentences. There is evidence in the literature and anecdotal evidence from workers in the field that young offenders are at particularly high risk of dying from drug overdose, violently or by suicide, yet deaths in this group have not yet been investigated in Australia. As far as we are aware, there are also no reports worldwide of standardised mortality rates for young offenders who have been in ....The proposal seeks funding to investigate the death rate in young people who have received custodial sentences. There is evidence in the literature and anecdotal evidence from workers in the field that young offenders are at particularly high risk of dying from drug overdose, violently or by suicide, yet deaths in this group have not yet been investigated in Australia. As far as we are aware, there are also no reports worldwide of standardised mortality rates for young offenders who have been incarcerated. A group of young people who have received their first custodial sentences between 1988 and 1999 in Victoria will be identified, starting with 10 year olds in 1988. Their details will then be matched with data held by The National Death index, housed at the Australian Institute of Health and Welfare, and with the Victorian Coroner's data in order to identify deaths that have occurred, the cause of death and the circumstances of death. This will provide an index of the excess deaths experienced by this group of young offenders compared with Victorian population data for the same age group and gender. Further analysis will elucidate cause specific mortality, will enable the identification of subgroups at particular risk and the examination of trends over time. The study will provide a solid foundation for health priorities, the development of interventions and policy in relation to young offenders. It will provide a resource for Australasia and be of worldwide interest. Juvenile offenders are a well-defined group who has extended contact with support services. There is a unique opportunity for the delivery of interventions aimed at improving the welfare and adult outcomes of this enormously disadvantaged and marginalised section of our community. The Centre for Adolescent Health, as the auspicing body for the Adolescent Forensic Health Service is in an excellent position to respond to this challenge.Read moreRead less
I am a molecular virologist studying the events of virus replication and virus-host interactions with the ultimate goal to understand the mechanisms determining viral pathogenesis and develop safe and effective vaccines.
The Genetics Governing The Specificity Of T Cell Receptors For Peptide-MHC
Funder
National Health and Medical Research Council
Funding Amount
$303,828.00
Summary
T lymphocytes play a pivotal role in the immune system by recognising virus-infected tissue through the use of highly specific cell surface receptors. These T cell receptors (TCR) recognise viral peptides (p) presented by MHC molecules on the surface of virus-infected cells. For a TCR to be successfully triggered, it must lock onto an exact 3-dimentional pMHC match. In this way, any given TCR must simultaneously recognise both the viral peptide and the MHC presenting it. Such recognition must be ....T lymphocytes play a pivotal role in the immune system by recognising virus-infected tissue through the use of highly specific cell surface receptors. These T cell receptors (TCR) recognise viral peptides (p) presented by MHC molecules on the surface of virus-infected cells. For a TCR to be successfully triggered, it must lock onto an exact 3-dimentional pMHC match. In this way, any given TCR must simultaneously recognise both the viral peptide and the MHC presenting it. Such recognition must be sensitive and precise since a false positive could result in destruction of healthy tissue. There are a huge variety of TCRs and pMHCs, but there are only a few examples where the precise molecular interactions within the TCR-pMHC complex are known. Surprisingly, these studies have shown very limited consistency in the way the TCRs bind the pMHCs and therefore, the structural rules that underlie why TCRs consistently bind MHC remains a mystery of critical importance to this fundamental feature of the immune system. In this proposal, we will attempt to elucidate the rules of TCR-pMHC engagement. Another question to be addressed in this proposal is: During a viral infection, why are certain TCRs chosen above others that also have the capacity to recognise the same viral peptide? By investigating exactly which feature-s of these receptors predisposes their supremacy, we may be better able to predict the outcome of a pathogen attack and to even one day build our own super receptors. Finally, this proposal will also investigate how natural mutations in TCR genes across the human population affect our individual responses to viruses. Overall, advances in each of these core areas of medical research will aid in the development of new intelligent vaccines and individualised drugs for the treatment of cancer and infectious disease.Read moreRead less