An X-ray crystallographic investigation into co-receptors on T-lymphocytes. T lymphocytes are an indispensable cellular component of the immune system. The normal process of T cell selection in the thymus, and the ability of mature T cells to respond to foreign antigens are governed by receptor recognition and co-receptor mediated events. The co-receptors encompass a wide spectrum of structurally diverse proteins that are involved in adhesion, co-ligation and signal transduction. This proposa ....An X-ray crystallographic investigation into co-receptors on T-lymphocytes. T lymphocytes are an indispensable cellular component of the immune system. The normal process of T cell selection in the thymus, and the ability of mature T cells to respond to foreign antigens are governed by receptor recognition and co-receptor mediated events. The co-receptors encompass a wide spectrum of structurally diverse proteins that are involved in adhesion, co-ligation and signal transduction. This proposal aims to investigate, using X-ray crystallography as the primary research tool, co- receptors located on T-lymphocytes. This work will gain fundamental insights into co-receptor function.Read moreRead less
Understanding the critical processes that control cell death and using this knowledge to kill cells that have evaded death. Cell death is essential for protecting the body against cancer, and defects in cell death pathways contribute to cancer progression. To design new and better cancer therapies we must understand the critical processes which control cell death, and develop effective ways to either reset, or bypass, defects in cell death pathways that contribute to cancer. The program as outl ....Understanding the critical processes that control cell death and using this knowledge to kill cells that have evaded death. Cell death is essential for protecting the body against cancer, and defects in cell death pathways contribute to cancer progression. To design new and better cancer therapies we must understand the critical processes which control cell death, and develop effective ways to either reset, or bypass, defects in cell death pathways that contribute to cancer. The program as outlined will elucidate the process of mitochondrial outer membrane permeabilization, a critical event in cell death by apoptosis, and determine how to kill cells in which this event is blocked.Read moreRead less
A New Model for 3D Migration Involving Claw Structures and Metalloproteinases. This proposal will revolutionize ideas related to cell movement through three-dimensional (3D) matrix. Our method in mimicking the body's dense 3D matrix environment have led to the discovery of a new cell structure called Claws, and the formulation of a new model for 3D invasion in high density matrix. We will study the genes that control this type of migration including those involved in the formation of the cell fr ....A New Model for 3D Migration Involving Claw Structures and Metalloproteinases. This proposal will revolutionize ideas related to cell movement through three-dimensional (3D) matrix. Our method in mimicking the body's dense 3D matrix environment have led to the discovery of a new cell structure called Claws, and the formulation of a new model for 3D invasion in high density matrix. We will study the genes that control this type of migration including those involved in the formation of the cell front (Claw region), the back of the cells and matrix digestion. This work will have significant impact on normal and pathological human conditions from immune responses to tissue regeneration and cancer.Read moreRead less
A Structural Investigation Into Events Within The Immunological Synapse. The proposed research program, using laboratory-based and synchrotron-based radiation, will provide significant fundamental insight into the processes that control infection. Investigating processes central to immunity is important, as it will further our understanding of these critically-important events. Such knowledge will increase Australia's international research standing, as well as having the potential to generat ....A Structural Investigation Into Events Within The Immunological Synapse. The proposed research program, using laboratory-based and synchrotron-based radiation, will provide significant fundamental insight into the processes that control infection. Investigating processes central to immunity is important, as it will further our understanding of these critically-important events. Such knowledge will increase Australia's international research standing, as well as having the potential to generate novel therapies, such as immunosuppressants.Read moreRead less
Elucidating the regulation of cell death by random mutagenesis of key apoptotic proteins. All organisms need to remove damaged or excessive cells. This cell death process is called apoptosis. Defects in apoptosis result in numerous diseases including cancer, and neurodegenerative and immune disorders. Determining how this process is regulated is of crucial importance for therapeutic intervention. We will utilise a powerful strategy to mutate proteins required for apoptosis so that they no longer ....Elucidating the regulation of cell death by random mutagenesis of key apoptotic proteins. All organisms need to remove damaged or excessive cells. This cell death process is called apoptosis. Defects in apoptosis result in numerous diseases including cancer, and neurodegenerative and immune disorders. Determining how this process is regulated is of crucial importance for therapeutic intervention. We will utilise a powerful strategy to mutate proteins required for apoptosis so that they no longer work, which will allow the identification of protein regions essential for cell death activity . This will lead to identification of potential drug targets to control apoptosis. Elucidating the mechanism of cell death will lead to the development of novel and improved therapies for diseases such as cancer and neurodegenerative disease.Read moreRead less
Role of the PU.1 transcription factor in regulating lymphoid development. Haemopoiesis is a tightly regulated process and provides an important model for our understanding and application of stem cell biology. Perturbation of early haemopoiesis results in a number of important disorders including leukaemia, anaemia and immunodeficiency. The application of stem cells to many disease conditions is currently being pursued, however, in order to develop therapeutic interventions knowledge of normal c ....Role of the PU.1 transcription factor in regulating lymphoid development. Haemopoiesis is a tightly regulated process and provides an important model for our understanding and application of stem cell biology. Perturbation of early haemopoiesis results in a number of important disorders including leukaemia, anaemia and immunodeficiency. The application of stem cells to many disease conditions is currently being pursued, however, in order to develop therapeutic interventions knowledge of normal cellular differentiation is crucial. The studies outlined here aim to contribute to the understanding of the these processes and hence help to provide the framework for future studies aimed at more directly altering cell fate decision for clinical applications. Read moreRead less
GENOMIC/PHENOMIC IDENTIFICATION AND CHARACTERISATION OF NOVEL HEMATOPOIETIC REGULATORS. Blood cells are fundamental to health. They play a vital role in maintaining the condition of tissues and organs, fight infections and are essential players in the body's response to injury. Understanding how blood cells are produced and how they function is critical to improving the treatment of disease. With the sequencing of the genome, we now have the tools we need to find the genes controlling these proc ....GENOMIC/PHENOMIC IDENTIFICATION AND CHARACTERISATION OF NOVEL HEMATOPOIETIC REGULATORS. Blood cells are fundamental to health. They play a vital role in maintaining the condition of tissues and organs, fight infections and are essential players in the body's response to injury. Understanding how blood cells are produced and how they function is critical to improving the treatment of disease. With the sequencing of the genome, we now have the tools we need to find the genes controlling these processes. This project will harness the power of modern genetic technologies to dissect the role of novel genes involved in blood cell formation and function, and will open up new therapeutic opportunities for treating the many diseases associated with dysregulation of this important cell system. Read moreRead less
Function and regulation of the Schlafen gene family: novel regulators of blood cell proliferation and function. The immediate outcomes of the proposed research will be in fundamental knowledge and understanding of important cellular and biological processes in which the Schlafen genes are involved. In particular, Schlafen genes are likely to play a role in inflammatory responses and in blood cell growth. These process clearly have relevance to a range of major human (and animal) diseases includ ....Function and regulation of the Schlafen gene family: novel regulators of blood cell proliferation and function. The immediate outcomes of the proposed research will be in fundamental knowledge and understanding of important cellular and biological processes in which the Schlafen genes are involved. In particular, Schlafen genes are likely to play a role in inflammatory responses and in blood cell growth. These process clearly have relevance to a range of major human (and animal) diseases including infectious disease, auto-immune disease and leukaemia, and thus a long-term outcome may be improved treatments for such disease. Read moreRead less
A proteomic approach to the identification of novel targets for allergy treatment. Eosinophils are involved in parasite immunity and in the pathology of allergic diseases including asthma. Eosinophil recruitment and activation is critical to their functional activity, but the relevant molecular mechanisms have not been fully elucidated. In the present proposal, a unique resource of eosinophils, at different stages of recruitment and activation, will be used for detailed proteomic analysis to ide ....A proteomic approach to the identification of novel targets for allergy treatment. Eosinophils are involved in parasite immunity and in the pathology of allergic diseases including asthma. Eosinophil recruitment and activation is critical to their functional activity, but the relevant molecular mechanisms have not been fully elucidated. In the present proposal, a unique resource of eosinophils, at different stages of recruitment and activation, will be used for detailed proteomic analysis to identify molecules and molecular pathways involved in eosinophil migration and activation. These studies may lead to novel anti-inflammatory strategies and more targeted drug treatments that will generate significant intellectual property and be of enormous benefit to allergy patients worldwide.Read moreRead less
Studies on the regulation of the pro-apoptotic protein Bim in mammalian development and cancer. This project is aimed at understanding the regulation of a gene, which is a tumour suppressor and is often mutated or down regulated in many different forms of cancers. A better understanding of how this gene works may eventually lead to better therapeutics to treat these cancers. This is relevant in the Australian context given that our aging population and obesity epidemics (the link between obesity ....Studies on the regulation of the pro-apoptotic protein Bim in mammalian development and cancer. This project is aimed at understanding the regulation of a gene, which is a tumour suppressor and is often mutated or down regulated in many different forms of cancers. A better understanding of how this gene works may eventually lead to better therapeutics to treat these cancers. This is relevant in the Australian context given that our aging population and obesity epidemics (the link between obesity, insulin resistance and various forms of cancers is well established) are leading to a rapid increase in new cancer cases, thus driving a rapid increase in demand for better treatments. This is particularly relevant in Indigenous health where obesity is on the rise following the transition from a traditional to an urban lifestyle.Read moreRead less