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
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
Functional characterization of SSB2: a novel single-stranded DNA binding protein. Defects in the DNA damage response pathway underpin many human genetic disorders and diseases. A detailed understanding of this pathway has enormous implications for future medicine. The proposed research will lead to functional characterization of a new protein, identify new concepts in DNA damage repair pathways, train young researchers and place Australia among the leaders in this internationally significant and ....Functional characterization of SSB2: a novel single-stranded DNA binding protein. Defects in the DNA damage response pathway underpin many human genetic disorders and diseases. A detailed understanding of this pathway has enormous implications for future medicine. The proposed research will lead to functional characterization of a new protein, identify new concepts in DNA damage repair pathways, train young researchers and place Australia among the leaders in this internationally significant and highly competitive area of research. It will underpin the national research priority of Promoting and Maintaining Good Health and help Australia capitalise on a plethora of opportunities for future economic and health benefits.Read moreRead less
Examining the relationship between error processing, cognitive control and emotion: a cognitive neuroscience approach. The proposed research aims to contribute to current scientific thinking on how the processing of errors influences self-monitoring and cognitive performance. The ability to monitor one's cognitive performance deteriorates with normal ageing, and is particularly affected in a range of clinical conditions, where it is a reliable predictor of a poor prognostic outcome. This project ....Examining the relationship between error processing, cognitive control and emotion: a cognitive neuroscience approach. The proposed research aims to contribute to current scientific thinking on how the processing of errors influences self-monitoring and cognitive performance. The ability to monitor one's cognitive performance deteriorates with normal ageing, and is particularly affected in a range of clinical conditions, where it is a reliable predictor of a poor prognostic outcome. This project aims to clarify understanding of the cognitive and neural processes underlying self-monitoring, as an important first step to improving rehabilitation and management methods for age-related impairments such as Alzheimer's disease, and prominent mental health conditions such as schizophrenia.Read moreRead less
An RNA interference based genetic screen for novel epigenetic modifiers involved in mammalian X inactivation. All the information required to form an adult human is contained in the DNA of the fertilized egg. Development is achieved by a complex orchestration of genes being switched on and off, controlled by proteins called epigenetic modifiers. Sometimes this goes awry, leading to disease. Despite their vital role, only around ten percent of the potential epigenetic modifiers have been characte ....An RNA interference based genetic screen for novel epigenetic modifiers involved in mammalian X inactivation. All the information required to form an adult human is contained in the DNA of the fertilized egg. Development is achieved by a complex orchestration of genes being switched on and off, controlled by proteins called epigenetic modifiers. Sometimes this goes awry, leading to disease. Despite their vital role, only around ten percent of the potential epigenetic modifiers have been characterized in humans, making it impossible to interpret how they work together, or when they fail. We will develop a novel screen-based technology to find hundreds more true epigenetic modifiers. This technology will aid us and other Australian scientists to understand the role of epigenetics in normal development and disease, ultimately leading to better public health.Read moreRead less
Socs proteins in development and disease. Socs proteins are a component of a pathway that is central to a range of developmental processes, including embryonic development. In addition, there is evidence that these proteins are perturbed in several disorders. This Project will enhance our understanding of the Socs proteins and their role in disease, and ultimately provide an opportunity to identify new therapeutic strategies.
Probing membrane rafts using surface-selective multi-dimensional microscopy. The results of this project will provide fundamental insights into the role played by domains in cell membranes in the regulation of membrane protein function. These insights will create new avenues in the biotechnology industry for development of novel therapeutics aimed at disruption of membrane protein-protein interactions that cause aberant cell signalling in disease states such as cancer.
Molecular signals that regulate the regenerative properties of intestinal epithelial cells. Most cancer deaths are due to the cancer spreading to other organs. Cancer is much more difficult to treat once it has spread to other organs in the body where the cancer cells can exist in a dormant state. Dormant cancer cells evade conventional anticancer treatment and can remain dormant for a very long time before they change back to a 'tumour-growing' state. An understanding of how the cancer initiati ....Molecular signals that regulate the regenerative properties of intestinal epithelial cells. Most cancer deaths are due to the cancer spreading to other organs. Cancer is much more difficult to treat once it has spread to other organs in the body where the cancer cells can exist in a dormant state. Dormant cancer cells evade conventional anticancer treatment and can remain dormant for a very long time before they change back to a 'tumour-growing' state. An understanding of how the cancer initiating (stem cell) property of tumour cells is maintained offers potential novel avenues to eliminate persistent cancer cells. This knowledge will ultimately lead to better management and treatment of cancer, and increase survival. An understanding of stem cell behaviour is also central to the control of degenerative conditions.Read moreRead less
The role of retinoic acid signalling in the development of the oesophageal epithelium. Oesophageal adenocarcinoma (OAC) is a disease with increasing incidence. The majority of patients with OAC are diagnosed when the cancer is at a late stage and therefore treatment options are limited, meaning the disease is almost invariably fatal. OAC arises from the precancerous condition, Barrett's oesophagus, which occurs as a consequence of chronic reflux, although the key processes driving its developmen ....The role of retinoic acid signalling in the development of the oesophageal epithelium. Oesophageal adenocarcinoma (OAC) is a disease with increasing incidence. The majority of patients with OAC are diagnosed when the cancer is at a late stage and therefore treatment options are limited, meaning the disease is almost invariably fatal. OAC arises from the precancerous condition, Barrett's oesophagus, which occurs as a consequence of chronic reflux, although the key processes driving its development are unknown. This project aims to better understand the critical first step in the progression to cancer and thus expand the scope for the development of therapies, particularly those aimed at early intervention, and tools that predict progression.Read moreRead less