Asymmetric Cell Divison In T Cell Development: Consequences For Immunity And Cancer
Funder
National Health and Medical Research Council
Funding Amount
$642,608.00
Summary
Human health depends upon the development of an immune system that can effectively control infection without damaging normal tissue. In this project, we assess a new paradigm by which immune cell development might be controlled, in which an immune cell precursor divides in such a way that its two daughters inherit different molecular constitutents that subsequently regulate the adoption of different cell fate. The likely consequences of this phenomonon on immunity and cancer will be explored.
In Vivo Imaging Of Protective And Malignant B Cell Function
Funder
National Health and Medical Research Council
Funding Amount
$431,412.00
Summary
B cells are responsible for producing antibody that protects us from infection. Disruption of healthy B cell function can lead to a myriad of diseases including immunodeficiency, autoimmunity and blood cancers such as leukaemia. The aim of my work is to use powerful microscopy to visualise how mutated B cells interact with their surrounding environment in real-time. These studies will allow the development of new treatments for cancer and immune conditions that target these interactions.
Investigating B Cell Development, Maintenance And High-affinity Antibody Production By ENU Mutagenesis
Funder
National Health and Medical Research Council
Funding Amount
$408,388.00
Summary
B cells are essential for the protection against infections. This application aims to identify new genes that are crucial for the development or function of B cells and will investigate how mutations in newly discovered genes contribute to defects in the development and function of B cells and the pathogenesis of B cell leukaemia.
Transcriptional Regulation Of Hematopoietic Commitment
Funder
National Health and Medical Research Council
Funding Amount
$289,985.00
Summary
Blood cell formation is a tightly regulated process and provides an important model for our understanding of blood homeostasis. Perturbations result in a number of disorders such as leukaemia. The application of stem cells to many diseases is being pursued; yet, to be successful knowledge of normal cellular behavior is crucial. I aim to improve our understanding of these processes and help to provide the framework for future studies aimed at more directly manipulating blood cell functions.
Structure And Composition Of The Pre-T Cell Receptor-CD3 Complex
Funder
National Health and Medical Research Council
Funding Amount
$307,946.00
Summary
In order to recognize a wide variety of pathogens, humans produce many different T cell receptors (TCRs) by the process of gene-rearrangement. However, gene-rearrangement may not always lead to a functioning TCR. We are studying the pre-TCR protein that is responsible for monitoring the success of gene-rearrangement and is thus essential for the formation of a robust immune system. Understanding pre-TCR function will lead to new treatments for immune related diseases.
Determining The Structure Of A Soluble Cytokine Receptor Complex
Funder
National Health and Medical Research Council
Funding Amount
$509,017.00
Summary
There is a pressing need to develop improved therapeutics to treat many forms of cancer and respiratory diseases. This proposal concerns the biochemical investigation of a group of protein hormones and their associated receptors that are implicated in blood cell cancers and for which current treatments are only partly effective . Our work will focus on determining the 3-dimensional shape and function of this group of proteins in complex with one another which will provide us with an understandin ....There is a pressing need to develop improved therapeutics to treat many forms of cancer and respiratory diseases. This proposal concerns the biochemical investigation of a group of protein hormones and their associated receptors that are implicated in blood cell cancers and for which current treatments are only partly effective . Our work will focus on determining the 3-dimensional shape and function of this group of proteins in complex with one another which will provide us with an understanding of how these proteins communicate with one another. This information may provide a basis for the design of new drugs that can specifically block the activity of these protein hormones, thereby providing new treatment possibilities for these blood cell cancers.Read moreRead less
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
Systematically Exploring The Contribution Of Immunoproteasome To Immunodominance And T Cell Function
Funder
National Health and Medical Research Council
Funding Amount
$499,860.00
Summary
Vaccine will help us to fight both infectious diseases and malignancy. However, there are few successful vaccines for infectious agents and there is simply no vaccine to cure any tumor at the moment. So, it is essential for us to learn the basics related to vaccine development. Killer T cells eliminate tumour cells or virally infected host cells by recognising fragments (epitopes) derived from tumour- or virus-derived proteins displayed on a host molecule called MHC. Normally multiple epitopes a ....Vaccine will help us to fight both infectious diseases and malignancy. However, there are few successful vaccines for infectious agents and there is simply no vaccine to cure any tumor at the moment. So, it is essential for us to learn the basics related to vaccine development. Killer T cells eliminate tumour cells or virally infected host cells by recognising fragments (epitopes) derived from tumour- or virus-derived proteins displayed on a host molecule called MHC. Normally multiple epitopes are generated as part of the protein recycling program referred as proteine degradation which is mainly conducted by bundled enzyme complex, called proteasome. Two major forms of proteasomes are expressed by most cells. One called house-keeping proteasome and the other, which replaces the house-keeping one during viral infections is called immunoproteasome. The role that the immunoproteasome plays during anti-viral and anti-tumoral immune responses is not fully understood. In addition, the immunoproteasome is also expressed by a few cell types that do not suppose to need it if its function is entirely to generate better epitopes for MHC to display. In this project, we will sytematically explore the contribution of the immunoproteasome to overall anti-viral and anti-tumoral immune responses in three mouse model systems. The shared feature of these systems is that multiple killer T cell epitopes have been defined, which could potentially provide us with very sensitive assessments. The three systems are anti-influenza, anti-vaccinia virus and anti-tumor antigen (NY-ESO-1) mouse models.Read moreRead less
MAIT cells are a recently discovered type of lymphocyte that plays a unique and important role in the immune system. However, these cells vary widely in number between healthy individuals, for reasons that are unclear. This project is designed to understand the factors that control the development of MAIT cells as a step toward regulating their numbers and activity.