Control of cell survival by the Bcl-2 protein family. The control of apoptosis is essential for homeostasis. It is now realized that deregulation of apoptosis is a hallmark of many cancers. In apoptosis, the Bcl-2 protein family plays a central role in determining if a cell lives or dies. My proposal aim is to provide a deeper understanding of how cell death and survival is controlled by the Bcl-2 family. These studies have notable implications for understanding normal cell death control as well ....Control of cell survival by the Bcl-2 protein family. The control of apoptosis is essential for homeostasis. It is now realized that deregulation of apoptosis is a hallmark of many cancers. In apoptosis, the Bcl-2 protein family plays a central role in determining if a cell lives or dies. My proposal aim is to provide a deeper understanding of how cell death and survival is controlled by the Bcl-2 family. These studies have notable implications for understanding normal cell death control as well as aid in the development of therapeutic agents such as ones to overcome the resistance to apoptosis, found in many types of cancer.Read moreRead less
Apoptotic signalling in virally infected and normal cells. Viral diseases contribute substantially to mortality and morbidity, in Australia and internationally. Emerging viral diseases, including H5N1 avian influenza, have the potential to severely impact on human health and the global economy. Concerns also exist that viruses may be used as bioweapons. This project seeks to define the mechanisms by which cell death occurs and is regulated in healthy cells, and how this is altered in virally inf ....Apoptotic signalling in virally infected and normal cells. Viral diseases contribute substantially to mortality and morbidity, in Australia and internationally. Emerging viral diseases, including H5N1 avian influenza, have the potential to severely impact on human health and the global economy. Concerns also exist that viruses may be used as bioweapons. This project seeks to define the mechanisms by which cell death occurs and is regulated in healthy cells, and how this is altered in virally infected or oncogenically transformed cells. Outcomes of this work may contribute to development of novel anti-cancer and anti-viral therapies, diagnostic reagents and vaccines.Read moreRead less
Mechanisms of cell death regulation by the Bcl-2 protein family. Through the proposed study, the expected outcome is a better understanding of the important process of how the Bcl-2 family of proteins interact with each to control cell death. Furthermore, as dysfunctional apoptosis signalling contributes to diseases such as autoimmune conditions, neurodegenerative disorders and cancer, a detailed and sound understanding of how the cell death machinery operates should enable the design of more ef ....Mechanisms of cell death regulation by the Bcl-2 protein family. Through the proposed study, the expected outcome is a better understanding of the important process of how the Bcl-2 family of proteins interact with each to control cell death. Furthermore, as dysfunctional apoptosis signalling contributes to diseases such as autoimmune conditions, neurodegenerative disorders and cancer, a detailed and sound understanding of how the cell death machinery operates should enable the design of more effective and importantly, safer therapies against these pathologies.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
Role of Histone deacetylase 3 (HDAC3) in intestinal epithelial cell homeostasis and tumorigenesis. Colon cancer is the most common cancer that affects men and women in Australia. Annually, in Victoria alone, more than 3400 people are diagnosed with colon cancer. Colon cancer arises through the accumulation of mutations in key genes over time. Identification of cancer causing genes provides the basis for the design of new cancer therapies. We recently identified a gene called Histone deacetylase ....Role of Histone deacetylase 3 (HDAC3) in intestinal epithelial cell homeostasis and tumorigenesis. Colon cancer is the most common cancer that affects men and women in Australia. Annually, in Victoria alone, more than 3400 people are diagnosed with colon cancer. Colon cancer arises through the accumulation of mutations in key genes over time. Identification of cancer causing genes provides the basis for the design of new cancer therapies. We recently identified a gene called Histone deacetylase 3 (HDAC3) as potentially involved in promoting colon cancer. The current proposal will now extend and validate this finding in mice. Importantly, drugs which inhibit HDAC3 have recently been developed for the treatment of cutaneous T-cell lymphoma. Defining the role HDAC3 plays in colon cancer will justify testing these drugs in colon cancer patients.Read moreRead less
Structural investigations into the regulation of programmed cell death. One in three men and one in four women in Australia will develop cancer by the age of 75 at current incidence rates. At its heart, cancer is a disease of uncontrolled cell proliferation. One of the body's main defence mechanisms against excess cell proliferation is Programmed Cell Death, a process which becomes dysfunctional in cancer cells. This work will provide three dimensional images of the machinery that controls Progr ....Structural investigations into the regulation of programmed cell death. One in three men and one in four women in Australia will develop cancer by the age of 75 at current incidence rates. At its heart, cancer is a disease of uncontrolled cell proliferation. One of the body's main defence mechanisms against excess cell proliferation is Programmed Cell Death, a process which becomes dysfunctional in cancer cells. This work will provide three dimensional images of the machinery that controls Programmed Cell Death. This information is critical for the development of drugs designed to re-initiate Programmed Cell Death in cancer cells.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
Insertion and assembly of proteins and lipids into biological membranes. We propose a multi-disciplinary approach to this fundamental biological problem and have established collaborations with experts in the USA, UK and Austria. Benefits from this research program fall into two discrete types. Firstly, detailed knowledge of the mechanism what is now a poorly understood biological process of cellular membrane assembly, with the prospects for using the knowledge for intervention into diseases suc ....Insertion and assembly of proteins and lipids into biological membranes. We propose a multi-disciplinary approach to this fundamental biological problem and have established collaborations with experts in the USA, UK and Austria. Benefits from this research program fall into two discrete types. Firstly, detailed knowledge of the mechanism what is now a poorly understood biological process of cellular membrane assembly, with the prospects for using the knowledge for intervention into diseases such as cancer. Secondly, excellent outcomes are provided for the training of postgraduate students and research staff. This project entails cutting edge technology, and the development of skills not common in Australia.Read moreRead less
Characterisation of molecular regulation of telomerase and telomeres by p53 in cell ageing. Telomeres, the ends of chromosomes shorten as a function of cell division, and thereby limit cell lifespan. Telomerase synthesizes telomeres and thus renders cells immortal. Recently, we found that p53, a protein with an important role in cell aging and in the uncontrolled growth of cancer, interacts with telomeres and telomerase by binding to the telomere proteins TRF1 and TRF2. This project will deciphe ....Characterisation of molecular regulation of telomerase and telomeres by p53 in cell ageing. Telomeres, the ends of chromosomes shorten as a function of cell division, and thereby limit cell lifespan. Telomerase synthesizes telomeres and thus renders cells immortal. Recently, we found that p53, a protein with an important role in cell aging and in the uncontrolled growth of cancer, interacts with telomeres and telomerase by binding to the telomere proteins TRF1 and TRF2. This project will decipher the mechanisms by which p53 regulates telomerase and telomeres, and establish the interrelationship of these proteins in regulating cell lifespan, death and immortalisation. It will provide important information for molecular intervention in cell ageing and immortalisation.Read moreRead less