New insights into mammalian gene transcription - the role of parafibromin. Increasing our knowledge of fundamental gene and protein interactions is imperative as we move into an era of targetted molecular therapies to treat disease. Cancer is at the forefront of these diseases with hope of improved treatments firmly based in understanding the basic cell biology of tumours. This proposal describes research into a protein called parafibromin. We propose that parafibromin acts in major pathways res ....New insights into mammalian gene transcription - the role of parafibromin. Increasing our knowledge of fundamental gene and protein interactions is imperative as we move into an era of targetted molecular therapies to treat disease. Cancer is at the forefront of these diseases with hope of improved treatments firmly based in understanding the basic cell biology of tumours. This proposal describes research into a protein called parafibromin. We propose that parafibromin acts in major pathways responsible for how a cell manages stress by regulating levels of proteins involved in the cellular stress response. Discoveries made during the course of this research will provide knowledge of gene and protein interactions that will be important in the future to develop anti-cancer therapies. 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
Characterisation of APC intracellular trafficking pathways. This is a fundamental research project aimed at addressing the cell biology of the APC tumour suppressor protein. APC gene mutations are directly linked to the development of colorectal cancer, a serious healthcare issue in Australia with approximately 12,400 new cases diagnosed each year and around 4,700 deaths. The severity of cases in men and women who develop colorectal cancer makes this a socio-economically serious health issue, an ....Characterisation of APC intracellular trafficking pathways. This is a fundamental research project aimed at addressing the cell biology of the APC tumour suppressor protein. APC gene mutations are directly linked to the development of colorectal cancer, a serious healthcare issue in Australia with approximately 12,400 new cases diagnosed each year and around 4,700 deaths. The severity of cases in men and women who develop colorectal cancer makes this a socio-economically serious health issue, and our project falls within the Research Priority 2: Promoting and Maintaining Good Health. If successful our project will identify localisation patterns and pathways of movement of APC within cells, which could ultimately help in development of treatments. Read moreRead less
Identifying the pathways employed by growth hormone to regulate the proliferation of adult neural stem cells. As stem cells underpin the maintenance and regeneration of the brain and are known to decline in number and competence with age; understanding exactly how these cells are regulated is of broad national benefit. Furthermore, given the regulatory role of growth hormone throughout the body, insights gained from this project should lead to the discovery of novel therapeutic targets both with ....Identifying the pathways employed by growth hormone to regulate the proliferation of adult neural stem cells. As stem cells underpin the maintenance and regeneration of the brain and are known to decline in number and competence with age; understanding exactly how these cells are regulated is of broad national benefit. Furthermore, given the regulatory role of growth hormone throughout the body, insights gained from this project should lead to the discovery of novel therapeutic targets both within and outside the nervous system, ultimately leading to preventative and restorative strategies for maintaining good health. Finally, this Proposal is of significant national benefit as it will undoubtedly advance our knowledge base in stem cell biology, helping to maintain Australia as a global leader in stem cell research.Read moreRead less
Unravelling transthyretin amyloid, bounding ahead using wallabies. Each protein in our body has a unique shape that enables it to function correctly. For unknown reasons, some proteins can change their shape, aggregate with other proteins and stick to the outside of cells of major organs or nerves. This prevents those cells from working properly and results in disease. Transthyretin is a protein that changes shape and aggregates in the heart of most people over the age of 70. The disease is call ....Unravelling transthyretin amyloid, bounding ahead using wallabies. Each protein in our body has a unique shape that enables it to function correctly. For unknown reasons, some proteins can change their shape, aggregate with other proteins and stick to the outside of cells of major organs or nerves. This prevents those cells from working properly and results in disease. Transthyretin is a protein that changes shape and aggregates in the heart of most people over the age of 70. The disease is called Senile Systemic Amyloidosis (SSA). It is not known how or why this happens. There is no cure or therapy. This project will use transthyretins from human and wallaby to explore a possible cause of SSA. If our hypothesis is correct, we will propose preventative actions to reduce the incidence of SSA in the future.Read moreRead less
Characterisation of a novel neural-specific ATPase in cholesterol transport. Ageing is determined by both genetic and metabolic factors. To a large part, the detailed mechanisms of ageing remain to be unexplored. Genetically, the timing of cell ageing entails the loss of telomeres (tips of chromosomes). However, the buildup of metabolic wastes resets the timing prematurely. Metabolic products accumulate from excess production or a shortfall of removal activity, which occurs in the various parts ....Characterisation of a novel neural-specific ATPase in cholesterol transport. Ageing is determined by both genetic and metabolic factors. To a large part, the detailed mechanisms of ageing remain to be unexplored. Genetically, the timing of cell ageing entails the loss of telomeres (tips of chromosomes). However, the buildup of metabolic wastes resets the timing prematurely. Metabolic products accumulate from excess production or a shortfall of removal activity, which occurs in the various parts of ageing cells in tissues such as brain. Traffic jams of cholesterol transport in the secretory pathway induce early ageing of the nerve cells. We investigate a novel mechanism controlling cholesterol transport in nerve cell ageing.Read moreRead less
Biological probes for understanding mammalian cellular transport mechanisms. Cellular components are moved around within cells by molecular motors. This fundamental transport mechanism depends on a network of tracks. Blocks in this cellular transport can result in a number of mammalian diseases, particularly within nerve cells. This project will increase our understanding of the mechanisms of cellular transport and, in particular, how molecular motors engage their cargo. This is essential ground ....Biological probes for understanding mammalian cellular transport mechanisms. Cellular components are moved around within cells by molecular motors. This fundamental transport mechanism depends on a network of tracks. Blocks in this cellular transport can result in a number of mammalian diseases, particularly within nerve cells. This project will increase our understanding of the mechanisms of cellular transport and, in particular, how molecular motors engage their cargo. This is essential groundwork for the development of drugs that target this transport mechanism.Read moreRead less
The MIA mitochondrial import pathway: structure and function. Our aging population is increasingly susceptible to mitochondrial disease and Australia is vulnerable to the associated economic and social burden. This research will benefit Australia by contributing to a knowledge-based economy; identifying new pathways that can be targeted for therapeutic intervention; developing smarter and faster hybrid approaches that strengthen Australia's basic and strategic research capability; and forging ne ....The MIA mitochondrial import pathway: structure and function. Our aging population is increasingly susceptible to mitochondrial disease and Australia is vulnerable to the associated economic and social burden. This research will benefit Australia by contributing to a knowledge-based economy; identifying new pathways that can be targeted for therapeutic intervention; developing smarter and faster hybrid approaches that strengthen Australia's basic and strategic research capability; and forging new international links. In the future, this research will lead to new collaborations between academia and industry and the discovery of potential new drugs that would benefit the health of Australians, benefit the economy of our healthcare system and provide potential economic benefits through royalty streams.Read moreRead less
The effects of alpha-2-macroglobulin on amyloid formation and toxicity. The expected outcomes will provide major advances in understanding how the abundant human blood protein alpha-2-macroglobulin influences the formation of protein aggregates that underpin a number of serious diseases (e.g. Alzheimer's disease). The linkages involved are of the highest calibre and will give the Fellowship holder a unique opportunity for training in environments that are truly internationally leading-edge. Fur ....The effects of alpha-2-macroglobulin on amyloid formation and toxicity. The expected outcomes will provide major advances in understanding how the abundant human blood protein alpha-2-macroglobulin influences the formation of protein aggregates that underpin a number of serious diseases (e.g. Alzheimer's disease). The linkages involved are of the highest calibre and will give the Fellowship holder a unique opportunity for training in environments that are truly internationally leading-edge. Furthermore, the very high novelty and broad significance of this work indicate that it will produce high-impact publications which will tangibly assist Australia being recognized as a major contributor to international research outcomes of the highest quality.Read moreRead less
Proteomics Analysis of Interactions Between Chaperonin 10 and Cell Surface Proteins. Specific interactions at the cell surface may induce downstream biological responses. In the case of chaperonin 10, Cpn10, interaction at the cell surface results in immunomodulation of the inflammatory response. Cell surface proteins that interact with Cpn10 have not been identified. This project will use chemical crosslinking and proteomic techniques to identify cell surface proteins that interact with Cpn10 a ....Proteomics Analysis of Interactions Between Chaperonin 10 and Cell Surface Proteins. Specific interactions at the cell surface may induce downstream biological responses. In the case of chaperonin 10, Cpn10, interaction at the cell surface results in immunomodulation of the inflammatory response. Cell surface proteins that interact with Cpn10 have not been identified. This project will use chemical crosslinking and proteomic techniques to identify cell surface proteins that interact with Cpn10 and structural features of Cpn10 involved in these interactions. These findings will providde leads for the development of immunomodulatory therapeutics based on Cpn10 interactions. Analytical technologies will be developed that are applicable to other interacting protein systems.Read moreRead less