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
Acquisition of the mitochondrial genome restores mitochondrial function. The aim of this project is to show that cancer cells with heavily damaged mitochondrial DNA (mtDNA) can acquire the mitochondrial genome from the host and that this results in the recovery of their mitochondrial function. The project is highly significant, as it aims to show in vivo mitochondrial transfer with functional consequences. The project aims to open a new avenue of research and could result in a shift in our under ....Acquisition of the mitochondrial genome restores mitochondrial function. The aim of this project is to show that cancer cells with heavily damaged mitochondrial DNA (mtDNA) can acquire the mitochondrial genome from the host and that this results in the recovery of their mitochondrial function. The project is highly significant, as it aims to show in vivo mitochondrial transfer with functional consequences. The project aims to open a new avenue of research and could result in a shift in our understanding of some features of cellular communication and how cells can overcome unfavourable situations.Read moreRead less
How do cells regulate redox environment at the subcellular level? Most organisms live in an aerobic environment that subjects their cells to reactive oxygen species. Reactive oxygen species have been proposed to lead to ageing, and in many diseases the balance between oxidising and reducing conditions (the redox environment) is perturbed. This research will identify how different cellular structures sense and maintain this redox homeostasis, not just in the whole cell, but within the different ....How do cells regulate redox environment at the subcellular level? Most organisms live in an aerobic environment that subjects their cells to reactive oxygen species. Reactive oxygen species have been proposed to lead to ageing, and in many diseases the balance between oxidising and reducing conditions (the redox environment) is perturbed. This research will identify how different cellular structures sense and maintain this redox homeostasis, not just in the whole cell, but within the different organelles in the cell. The work will help identify which cell compartments and processes are affected in different disease states and provide a fundamental understanding of how cells coordinate their different organelles to maintain the balance between oxidising and reducing conditions.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
Integration of Cellular Gene Regulation Processes. This research program aims to identify specific transcriptional regulatory networks in yeast, to determine how some of these networks interact with each other and within these networks to identify the roles of genes whose functions are currently unknown. It will identify systems regulating genes concerned with one-carbon metabolism, cellular responses to oxidative stress and developmental changes associated with meiosis. It will provide a fra ....Integration of Cellular Gene Regulation Processes. This research program aims to identify specific transcriptional regulatory networks in yeast, to determine how some of these networks interact with each other and within these networks to identify the roles of genes whose functions are currently unknown. It will identify systems regulating genes concerned with one-carbon metabolism, cellular responses to oxidative stress and developmental changes associated with meiosis. It will provide a framework to test regulatory network models and to analyse the molecular basis of interactions between control systems. This research will eventually provide the ability to predict how cells respond to drugs and other environmental stimuli.Read moreRead less
Cystine flux and hydrogen peroxide breakdown in reuteri group lactobacilli. We have discovered, and aim to fully dissect a novel function of reuteri group lactobacilli. These microbes inhabit the surfaces of the gastrointestinal and reproductive tracts of humans and are also used as probiotics, and in the dairy industry. This function mediates the production and breakdown of large amounts of hydrogen peroxide, cystine and thiols. These are highly bioactive and affect human cells and other bacter ....Cystine flux and hydrogen peroxide breakdown in reuteri group lactobacilli. We have discovered, and aim to fully dissect a novel function of reuteri group lactobacilli. These microbes inhabit the surfaces of the gastrointestinal and reproductive tracts of humans and are also used as probiotics, and in the dairy industry. This function mediates the production and breakdown of large amounts of hydrogen peroxide, cystine and thiols. These are highly bioactive and affect human cells and other bacteria at the surfaces of the gastrointestinal and reproductive tracts, and thiols are also flavourants in dairy products. Our research will inform the rational development of probiotics, the management and treatment of unpleasant conditions such as Crohn's disease and bacterial vaginosis, and innovation in dairy fermentations.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
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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Comparative toxicology of a fumigant and gasotransmitters: Testing a new model of fumigant toxicity in Caenorhabditis elegans. Fumigants share physical, chemical and functional properties with a medically important class of signalling molecules called gasotransmitters. This project proposes that the toxicity of fumigants is directly caused by their ability to mimic and disrupt gasotransmitter signalling. This project will test this hypothesis using the fumigant phosphine, a chemical that protect ....Comparative toxicology of a fumigant and gasotransmitters: Testing a new model of fumigant toxicity in Caenorhabditis elegans. Fumigants share physical, chemical and functional properties with a medically important class of signalling molecules called gasotransmitters. This project proposes that the toxicity of fumigants is directly caused by their ability to mimic and disrupt gasotransmitter signalling. This project will test this hypothesis using the fumigant phosphine, a chemical that protects the vast majority of the world grain supply from insect pests. This work will show us what makes a fumigant toxic. This knowledge will facilitate the discovery and effective deployment of new fumigants.Read moreRead less