The Role Of C-Cbl In The Regulation Of T Cell Signalling And Development
Funder
National Health and Medical Research Council
Funding Amount
$527,250.00
Summary
c-Cbl is a member of a multi-adaptor protein family that can interact with many signalling proteins via its different domains. Cbl proteins have been implicated as negative regulators of signalling pathways involving protein tyrosine kinases (PTKs). PTKs are enzymes which add phosphate groups to tyrosine residues on other protein substrates, and the process of tyrosine phosphorylation acts as a potent biochemical switch to turn signalling cascades on and off. Studies of Cbl-deficient (knockout) ....c-Cbl is a member of a multi-adaptor protein family that can interact with many signalling proteins via its different domains. Cbl proteins have been implicated as negative regulators of signalling pathways involving protein tyrosine kinases (PTKs). PTKs are enzymes which add phosphate groups to tyrosine residues on other protein substrates, and the process of tyrosine phosphorylation acts as a potent biochemical switch to turn signalling cascades on and off. Studies of Cbl-deficient (knockout) mice show that Cbl proteins are important in regulating the development of, and signalling by, cells of the immune system called T cells. c-Cbl knockout mice show greatly enhanced PTK-signalling responses and deregulated activity of a PTK called ZAP-70. The mechanism of this is not known, but analysis of a c-Cbl mutant mouse shows that this is not dependent on the tyrosine kinase binding (TKB) domain of c-Cbl. Therefore other functional domains of Cbl must be responsible for the increased signalling response in the c-Cbl knockout mouse. One candidate is the highly conserved RING finger domain which can modify Cbl-associated PTKs by addition of ubiquitin molecules. Ubiquitination of a protein often, but not always, leads to its degradation, and this could be how Cbl controls the strength and duration of signalling in T cells. However there may be other functions of the conserved RING finger yet to be identified. c-Cbl itself is prominently and very rapidly modified by tyrosine phosphorylation on tyrosine 737 by the Fyn PTK following T cell activation, but the role of this modification is not known and could also be essential for c-Cbl s function in T cells. We plan to investigate the roles of the RING finger domain and Fyn-mediated tyrosine phosphorylation in c-Cbl regulation of T cell signalling by analyzing knock-in mice that carry specific mutations disrupting the RING finger or tyrosine 737 in the c-Cbl gene.Read moreRead less
I am a Clinical Immunologist, Immunopathologist, clinical researcher and laboratory scientist exploring the interactions between T cell and viral infections. My area of particular interest is the mechanisms by which HIV infection subverts effective T cel
Functional Aspects Of CD52 Signalling In Immune Regulation
Funder
National Health and Medical Research Council
Funding Amount
$133,351.00
Summary
Autoimmune disease, such as Rheumatoid arthritis, Type 1-Diabetes, Lupus and Multiple Sclerosis, is caused by disruptions in the normal control of the immune system. A type of cell called a regulatory T-cell can prevent these damaging immune reactions. However, we do not know how T-cells do this. CD52 is a protein found on the surface of T-cells. Our preliminary work shows that CD52 also suppresses these damaging immune responses. This project researches how CD52 influences the immune system.
A novel link between metabolism and host defence. This project aims to delineate how a protein modification that consists of the addition of a small sugar to cellular proteins, known as O-GlcNAcylation, provides a link between metabolism and complex cell functions. The model for these studies is a cell type of the immune system known as dendritic cells. Upon encountering pathogens these cells undergo metabolic changes that increase the rate of O-GlcNAcylation of proteins involved in immune respo ....A novel link between metabolism and host defence. This project aims to delineate how a protein modification that consists of the addition of a small sugar to cellular proteins, known as O-GlcNAcylation, provides a link between metabolism and complex cell functions. The model for these studies is a cell type of the immune system known as dendritic cells. Upon encountering pathogens these cells undergo metabolic changes that increase the rate of O-GlcNAcylation of proteins involved in immune responses, altering their function. This project will study how O-GlcNAcylation works and is regulated. The project expects to develop new technology and provide high-level training, increasing the competitiveness of the strategic biotechnology sector in AustraliaRead moreRead less
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
Investigations Into The Biology And Functionality Of The Human T Cell Receptor
Funder
National Health and Medical Research Council
Funding Amount
$424,262.00
Summary
T lymphocytes play a pivotal role in the immune system by recognising virus-infected tissue and tumour cells through the use of specific cell surface receptors called T cell receptors (TCR). This project will study why partcular TCRs are used by the immune system, and will also examine the specificity of T cell recognition by determine the range of molecules an individual T cell can recognise. The work will aid in the development of new intelligent vaccines for cancer and infectious disease.
Defining The Roles Of The Chemotactic Receptor EBI2 For The Regulation Of Leukocyte Migration And The Generation Of Immunity
Funder
National Health and Medical Research Council
Funding Amount
$421,747.00
Summary
The proposed study aims at improving our understanding of the role of the immune cell receptor Epstein-Barr virus-induced gene 2 (EBI2) in guiding the movement of white blood cells during immune responses. The project will investigate the function of EBI2 in the control of infectious diseases and its regulation on human immune cells. These insights have the potential to create new therapeutic approaches to treat human autoimmune and inflammatory diseases and improve vaccine design.