Interplay Between Metabolic Reprogramming And Oncogenic Signalling In The Cellular Response To Chemotherapy
Funder
National Health and Medical Research Council
Funding Amount
$654,035.00
Summary
Chemotherapy resistance is a major barrier to the treatment of triple-negative breast cancer (TNBC). We seek to uncover an intimate link between cell metabolism and oncogenic signalling pathways in regulating the cellular response to chemotherapy. Our studies will identify a critical mechanism limiting the therapeutic efficacy of chemotherapy and investigate combination therapy strategies that could improve the treatment of TNBC.
The effect of mitochondrial and nuclear-cytoplasmic variation on longevity, metabolism and stress resistance in Drosophila. Much research points to a major role of free radical damage in aging, thus the belief that antioxidants might be beneficial in delaying aging. Free radicals are mostly formed in the subcellular organelles which consume oxygen and produce energy, and this may be the major site of age-related damage. This project seeks to understand the degree to which variation among these ....The effect of mitochondrial and nuclear-cytoplasmic variation on longevity, metabolism and stress resistance in Drosophila. Much research points to a major role of free radical damage in aging, thus the belief that antioxidants might be beneficial in delaying aging. Free radicals are mostly formed in the subcellular organelles which consume oxygen and produce energy, and this may be the major site of age-related damage. This project seeks to understand the degree to which variation among these subcellular organelles affect free radical damage and aging, using the fruitfly Drosophila melanogaster as a model organism.Read moreRead less
Molecular Genetic Analysis of Genes Regulating Metabolism in the Fungus Aspergillus nidulans. Filamentous fungi can use a wide variety of sources of carbon and nitrogen. In order to grow on these compounds metabolism is adjusted in response to changes in nutrient availability. Patterns of genome expression are altered by signalling to global regulatory genes which control the transcription of genes producing enzymes appropriate to the substrates available. This is of fundamental significance to ....Molecular Genetic Analysis of Genes Regulating Metabolism in the Fungus Aspergillus nidulans. Filamentous fungi can use a wide variety of sources of carbon and nitrogen. In order to grow on these compounds metabolism is adjusted in response to changes in nutrient availability. Patterns of genome expression are altered by signalling to global regulatory genes which control the transcription of genes producing enzymes appropriate to the substrates available. This is of fundamental significance to the physiology and development of fungi which include devastating pathogens and species used in industrial microbiology. This project aims to use the excellent molecular genetics of the model fungus Aspergillus nidulans to investigate the strategies employed and the mechanisms involved.Read moreRead less
Glutathione, a major antioxidant in plants: translocation between tissues and transport within cells. Plants are continually exposed to environmental stress. In agriculture this may include high and low temperature, pathogens, soil toxicity and excess light. The ways in which plants deal with environmental stress influence their productivity. Understanding these mechanisms is an important goal that can contribute to better strategies to manage plant responses to environmental stress in agricultu ....Glutathione, a major antioxidant in plants: translocation between tissues and transport within cells. Plants are continually exposed to environmental stress. In agriculture this may include high and low temperature, pathogens, soil toxicity and excess light. The ways in which plants deal with environmental stress influence their productivity. Understanding these mechanisms is an important goal that can contribute to better strategies to manage plant responses to environmental stress in agricultural species.Read moreRead less
Global genetic regulation of carbon metabolism in filamentous fungi. Fungi are of great importance in medicine, agriculture and industry. They are used extensively for food, antibiotic and chemical production and, increasingly, for generating cheap substrates for bioethanol. However many are serious pathogens of plants and humans. Understanding how fungi control their metabolism is of fundamental importance for their more effective use or control. This project takes advantage of a fungus that is ....Global genetic regulation of carbon metabolism in filamentous fungi. Fungi are of great importance in medicine, agriculture and industry. They are used extensively for food, antibiotic and chemical production and, increasingly, for generating cheap substrates for bioethanol. However many are serious pathogens of plants and humans. Understanding how fungi control their metabolism is of fundamental importance for their more effective use or control. This project takes advantage of a fungus that is easily studied in the laboratory by advanced genetic techniques to identify the ways in which genes are turned on and off in response to changes in the nutrients available. By comparing DNA sequences the results are readily applied to fungi of economic importance.Read moreRead less
Testing the free radical theory of aging: do indicators of oxidative damage predict lifespan? Because of the Free Radical Theory of Aging, many millions of dollars are spent around the world on dietary antioxidants of unproven efficacy. Many millions of research dollars are spent providing support for this theory but few studies test it rigorously. The first major benefit of this research is worldwide; to refute, or to substantially enhance and focus the current support for the Free Radical Theo ....Testing the free radical theory of aging: do indicators of oxidative damage predict lifespan? Because of the Free Radical Theory of Aging, many millions of dollars are spent around the world on dietary antioxidants of unproven efficacy. Many millions of research dollars are spent providing support for this theory but few studies test it rigorously. The first major benefit of this research is worldwide; to refute, or to substantially enhance and focus the current support for the Free Radical Theory. This should help to rationalise and direct funding supplied to these areas. The second benefit is for Australia: aging is a fruitful area for research because of the high general public interest and for training because of its multidisciplinary nature, and funding in Australia is very low by international standards. Read moreRead less
Cytopathological roles of AMPK in mitochondrial dysfunction. This research project will benefit the Australian community by deepening our understanding of mitochondrial and neurodegenerative diseases. These diseases are incurable and treatment options are limited. The knowledge gained in this project should assist in the development of new or improved treatments. The project will also contribute to the training of young scientists in biomedical research and will enhance Australia's international ....Cytopathological roles of AMPK in mitochondrial dysfunction. This research project will benefit the Australian community by deepening our understanding of mitochondrial and neurodegenerative diseases. These diseases are incurable and treatment options are limited. The knowledge gained in this project should assist in the development of new or improved treatments. The project will also contribute to the training of young scientists in biomedical research and will enhance Australia's international scientific reputation because it involves a significant and novel biomedical discovery.
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Autophagic vacuole formation in mammalian skeletal muscle; role of FOXO proteins. Loss of muscle tissue is a hallmark of many common health problems including cancer, HIV-Aids and renal failure. Recently, we identified that a family of transcription factors termed the forkhead box class-O (FOXO) winged helix transcription factors are key regulators of both anabolic (building) and catabolic (wasting) signalling pathways. This project will investigate the molecular regulation of cell integrity by ....Autophagic vacuole formation in mammalian skeletal muscle; role of FOXO proteins. Loss of muscle tissue is a hallmark of many common health problems including cancer, HIV-Aids and renal failure. Recently, we identified that a family of transcription factors termed the forkhead box class-O (FOXO) winged helix transcription factors are key regulators of both anabolic (building) and catabolic (wasting) signalling pathways. This project will investigate the molecular regulation of cell integrity by FOXO proteins. Although very basic in nature, these projects will identify how FOXO proteins regulate muscle cell building and wasting and, therefore, present a potential therapeutic target for muscle wasting diseases, making this project highly significant.Read moreRead less
Plant Genes Conferring Resistance to Ultraviolet Radiation. Ultraviolet (UV) radiation induces DNA damage that can decrease plant growth and productivity. Our aim is to begin deciphering the mechanisms responsible for the UV resistance phenotype in plants by: 1) isolating genes that control processing of UV-induced DNA damage; 2) determining the influence of UV on gene activity; and 3) elucidating the functions and essential interactions of the gene products. The results of this study will help ....Plant Genes Conferring Resistance to Ultraviolet Radiation. Ultraviolet (UV) radiation induces DNA damage that can decrease plant growth and productivity. Our aim is to begin deciphering the mechanisms responsible for the UV resistance phenotype in plants by: 1) isolating genes that control processing of UV-induced DNA damage; 2) determining the influence of UV on gene activity; and 3) elucidating the functions and essential interactions of the gene products. The results of this study will help us understand how these genes operate to produce the UV resistance phenotype. This new knowledge will facilitate eventual engineering of plants to increase agricultural productivity by enhancing resistance to solar UV radiation.Read moreRead less
Iron, ferroptosis and the biology of ageing. This project aims to determine how and when regulation of iron is lost. Failing iron metabolism during life may dictate the rate of ageing by driving a newly discovered cell death program. Combining biology, chemistry and physics, this collaborative project aims to transform the understanding of the fundamental mechanisms of biological ageing. Anticipated outcomes include new assays for measuring iron in biology and identification of potential pathway ....Iron, ferroptosis and the biology of ageing. This project aims to determine how and when regulation of iron is lost. Failing iron metabolism during life may dictate the rate of ageing by driving a newly discovered cell death program. Combining biology, chemistry and physics, this collaborative project aims to transform the understanding of the fundamental mechanisms of biological ageing. Anticipated outcomes include new assays for measuring iron in biology and identification of potential pathways that regulate death signaling and lifespan. Outcomes will benefit life sciences and biotechnology industries.Read moreRead less