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Investigating the evolution of innate and adaptive cellular immunity. This proposal aims to assess the impact of geographical and genetic isolation of the Australian Indigenous population on adaptive and innate immune systems. The project will use novel DNA sequencing approaches to generate the high resolution sequences of two genetic loci that regulate innate and adaptive immune responses, the major histocompatibility complex locus and the killer cell immunoglobulin-like receptor locus. In an i ....Investigating the evolution of innate and adaptive cellular immunity. This proposal aims to assess the impact of geographical and genetic isolation of the Australian Indigenous population on adaptive and innate immune systems. The project will use novel DNA sequencing approaches to generate the high resolution sequences of two genetic loci that regulate innate and adaptive immune responses, the major histocompatibility complex locus and the killer cell immunoglobulin-like receptor locus. In an initial screen, distinct variants and combinations of these genes were identified. This project aims to interrogate how variation in these critical genes impacts on the function of cytotoxic lymphocytes, providing insights into the evolutionary drivers of immune recognition mechanisms.Read moreRead less
Identification Of The Conformation Dependant Targets Of Autoimmune Disease Linked Variation In Human Regulatory T Cells
Funder
National Health and Medical Research Council
Funding Amount
$1,001,815.00
Summary
Specialised immune cells called regulatory T cells act as the policemen of the immune system, preventing the immune system attacking itself, but still fighting infections. If these cells do not work properly, autoimmune diseases such as type 1 diabetes or IBD can arise, because of immune attack on normal body tissue by mistake. In order to explain how this goes wrong we need to carefully identify all of the gene interactions in these cells including interactions over long distances in the DNA.
Autoimmune diseases are those caused by the body's immune system attacking the body's own tissues. One group of autoimmune diseases, termed the thyrogastric cluster appear to share genetic risk factors, because they tend to occur together - either in the same patient, or else in families. Some of the diseases within the thyrogastric cluster are known to be very complex genetically, while others appear to be much less complex. Furthermore, some animal models of autoimmune diease are genetically s ....Autoimmune diseases are those caused by the body's immune system attacking the body's own tissues. One group of autoimmune diseases, termed the thyrogastric cluster appear to share genetic risk factors, because they tend to occur together - either in the same patient, or else in families. Some of the diseases within the thyrogastric cluster are known to be very complex genetically, while others appear to be much less complex. Furthermore, some animal models of autoimmune diease are genetically simpler still. We have chosen to study the genetics of gastritis in mice that have had their thymuses removed on the third day of life, because this model has relatively few genes involved; we have found that only 4 genes affect the risk of disease. This means that it will give us the optimum chance of identfiying at least one of these genes. The methods used involve both selective breeding techniques and generating special gene transfer mice in which individuals from one strain will carry the inserted genes from another. In this way, we can identify exactly which genes affect the risk of disease. Once identified, the gene sequences will help us determine if the same gene plays a role in human disease, and if so, to develop new diagnostic tests and therapies.Read moreRead less
Genetic Determinants Of Interleukin-10 Response After Infectious Stimuli
Funder
National Health and Medical Research Council
Funding Amount
$276,000.00
Summary
Interleukin-10 is a key protein in the immune defense against infection, being the principal brake for the immune response. An diminished production of interleukin-10 has been implicated as a major cause of a number of devestating medical conditions including septic shock and acute respiratory distress syndrome. An excessive production of interleukin-10 may also be very harmful, and may be the primary cause of the reduction in immune function in many critically ill patients that leads to hospita ....Interleukin-10 is a key protein in the immune defense against infection, being the principal brake for the immune response. An diminished production of interleukin-10 has been implicated as a major cause of a number of devestating medical conditions including septic shock and acute respiratory distress syndrome. An excessive production of interleukin-10 may also be very harmful, and may be the primary cause of the reduction in immune function in many critically ill patients that leads to hospital acquired infections. These potential key roles of interleukin-10 in seriously ill patients makes it an attractive candidate to target for immune therapies. However, past experience with trials of immune-based therapies such as tumor necrosis factor alpha have taught us that we need to be much better at predicting individual immune responses if we are to 'interfere' with the immune system successfully. In the case of interleukin-10 there is substantial individual variation in the amount produced, with studies suggesting up to 70% of this variation is due to genetic differences. This project will establish the basis for this genetic variation by identiying both the genetic markers of high and low interleukin-10 response and the mechanisms by which these genetic markers change interleukin-10 production. This information will not only enable us to better target patients who may need an 'adjustment' of their immune function, but may also lead to novel therapeutic targets or therapeutic agents.Read moreRead less
Connections between nerve cells in the brain often occur onto enlarged protrusions called dendritic spines. This proposal will investigate the properties of dendritic spines, and relate differences in spine properties to synaptic plasticity. This information can be used to better understand and treat neurological disorders associated with spine malfunction, as occur in some forms of mental retardation, and may help with understanding the memory loss that occurs during ageing and dementia.
The Genetics And Mechanisms Of Resistance To The Zoonotic Highly Pathogenic Influenza Virus In Avian Species
Funder
National Health and Medical Research Council
Funding Amount
$337,373.00
Summary
Highly pathogenic avian influenza (HPAI) poses a serious pandemic risk. This project will investigate the genetic basis and mechanisms underlying resistance to HPAI in birds. It will explore the role of immune genes in resistance to HPAI in six bird species which vary in their susceptibility to HPAI. Functional tests of resistance genes will be performed to determine how these genes can provide resistance to HPAI. This study will assist in the development of strategies to mitigate disease risks.
Transcriptional And Metabolic Regulation Of Effector And Memory Lymphocyte Differentiation
Funder
National Health and Medical Research Council
Funding Amount
$707,370.00
Summary
I am an internationally recognized expert in the field of lymphocyte biology. My work has shed light on antibody production, T cell responses and immune pathology. Specifically, I have identified molecular regulators that link antigen recognition, lymphocyte population expansion, cellular metabolism and effector function. My ongoing work focusses on the development and function of several critically important cell types, including tissue resident lymphocytes and regulatory T cells.
Evolution of immunoregulatory networks: preventing autoimmunity at the expense of perpetuating chronicity in persistent infections. Chronic pathogens like HIV take advantage of human genes that regulate immune responses, which evolved to prevent autoimmunity, enabling them to evade eradication. This project defines the nature and interplays between these genes and will provide valuable clues as to how immunity can be manipulated to promote clearance of persistent infections.
Understanding The Role Of Three-dimensional Genome Organisation In B Cell Lineage Commitment And Leukaemia.
Funder
National Health and Medical Research Council
Funding Amount
$318,768.00
Summary
Every one of your nuclei contain 2 metres of DNA. This DNA is 300,000 times longer than the nucleus itself. In order to fit into this space, while maintaining access to crucial genes, the DNA forms a fantastically ordered three-dimensional structure. This intricate organisation is crucial to health, with even minute changes driving diseases, such as cancer and heart disease. We propose using new technology to understand how this organisation changes during immune cell development and leukaemia.