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Elucidating Metabolic Dysregulation In Alzheimer’s Disease: Profiling The Peripheral Immune Cell Lipidome To Unravel Pathological Mechanisms.
Funder
National Health and Medical Research Council
Funding Amount
$645,205.00
Summary
Both the immune system and lipid metabolism have been identified to be important in Alzheimer’s disease (AD). With the failures of all clinical trials attempting to treat AD, we seek to determine a way to both better diagnose individuals with AD and to identify people at increased risk. This project uses a novel profiling technique to characterise the lipid composition of immune cells to diagnose, predict risk, monitor the disease and to identify potential disease modifying therapeutic targets.
Navigating flux control through a branched metabolic pathway. This project aims to uncover control points and programmes in the mevalonate pathway, an important cellular metabolic pathway that produces cholesterol and isoprenoids. Knowledge of its regulation is largely restricted to just one enzyme (HMGCR). This project will determine how regulation of the later sterol-producing segment affects the early isoprenoid-segment of the mevalonate pathway; investigate how the two alternate routes to ch ....Navigating flux control through a branched metabolic pathway. This project aims to uncover control points and programmes in the mevalonate pathway, an important cellular metabolic pathway that produces cholesterol and isoprenoids. Knowledge of its regulation is largely restricted to just one enzyme (HMGCR). This project will determine how regulation of the later sterol-producing segment affects the early isoprenoid-segment of the mevalonate pathway; investigate how the two alternate routes to cholesterol synthesis operate and are regulated; and explore a co-ordinated and possibly co-operative transcriptional program. This project is expected to provide valuable knowledge of how cells control these critical lipids, which will ultimately inform better ways to treat diseases of cholesterol excess and defects in this pathway.Read moreRead less
Purification and bioactivity of legume protein as nutritional supplements . Lupin seed is a major Australian high protein legume crop, undervalued at only ~$200 tonne due to its use as an animal feed. However this project aims to add value to the crop by designing a scalable food-grade and commercialisable technology to purify the protein gamma-conglutin from lupin seed waste as a nutraceutical for human blood glucose control. The process optimisation and mechanism of action for gamma-congluti ....Purification and bioactivity of legume protein as nutritional supplements . Lupin seed is a major Australian high protein legume crop, undervalued at only ~$200 tonne due to its use as an animal feed. However this project aims to add value to the crop by designing a scalable food-grade and commercialisable technology to purify the protein gamma-conglutin from lupin seed waste as a nutraceutical for human blood glucose control. The process optimisation and mechanism of action for gamma-conglutin will be informed by proteomic analysis and cellular studies. From the project farmers may benefit through adding a premium to their crop value, a new gamma-conglutin purification technology will be available for processors to commercialise and consumers will have a natural product to help their blood glucose control.Read moreRead less
Discovery of new metabolic functions in Plasmodium parasites. This research will provide new understanding about the metabolism of parasites, such as those that cause malaria. These parasites have evolved bespoke metabolic networks to survive in diverse host environments including mosquitos and humans. Previous studies have revealed many unique genes and metabolites in these organisms, but their biochemical function is not known. This project will use state-of-the-art metabolomics and proteomics ....Discovery of new metabolic functions in Plasmodium parasites. This research will provide new understanding about the metabolism of parasites, such as those that cause malaria. These parasites have evolved bespoke metabolic networks to survive in diverse host environments including mosquitos and humans. Previous studies have revealed many unique genes and metabolites in these organisms, but their biochemical function is not known. This project will use state-of-the-art metabolomics and proteomics technology to accurately identify novel metabolites produced by the parasites, and discover the enzymes that are responsible for their synthesis. This work will not only advance our understanding of cellular metabolism, but will provide new opportunities for future biotechnology applications.Read moreRead less
Signaling in the crypt: a novel metabolic pathway in intestinal stem cells. The gut is the most rapidly renewing tissue in the body, driven by a highly active stem cell niche. Bile acids are emerging as critical regulators of this stem cell niche and disruption of bile acid homeostasis has profoundly adverse effects on intestinal renewal and hence gut health. We are addressing a critical gap in our understanding of how bile acids are controlled within stem cell niche. The aim of the project is ....Signaling in the crypt: a novel metabolic pathway in intestinal stem cells. The gut is the most rapidly renewing tissue in the body, driven by a highly active stem cell niche. Bile acids are emerging as critical regulators of this stem cell niche and disruption of bile acid homeostasis has profoundly adverse effects on intestinal renewal and hence gut health. We are addressing a critical gap in our understanding of how bile acids are controlled within stem cell niche. The aim of the project is to define the critical role of a novel enzyme called UGT8 in controlling intestinal stem cell response to bile acids; this is achieved by modulating UGT8 activity in intestinal stem cell models and determining the effects on stem cell function and the key signalling pathways that control intestinal homeostasis and renewal.Read moreRead less
Improving the Sustainability of Australian Livestock Production Systems. The sustainability of livestock production systems must urgently be improved. This Future Fellowship builds upon Dr Zamira Gibb's portfolio of high-impact research to deliver extension and adoption activities which will improve the outcomes of cattle and horse selective breeding programs; allowing the dissemination of low-methane genetics to remote Northern Australian cattle breeding regions, reducing wastage of breeding ho ....Improving the Sustainability of Australian Livestock Production Systems. The sustainability of livestock production systems must urgently be improved. This Future Fellowship builds upon Dr Zamira Gibb's portfolio of high-impact research to deliver extension and adoption activities which will improve the outcomes of cattle and horse selective breeding programs; allowing the dissemination of low-methane genetics to remote Northern Australian cattle breeding regions, reducing wastage of breeding horses and dairy cattle, and improving foal heath and offspring longevity. This project will address the environmental, ethical, and economic concerns which threaten the sustainability of these culturally significant livestock industries which are the cornerstone of everyday life in regional communities. Read moreRead less
Augmenting the activity of glyoxalase-1 to increase dicarbonyl clearance . Reactive intermediates generated during our metabolism contribute to ageing. Glyoxalase-1 is a key defence enzyme against these toxic intermediates and therefore ageing itself. This project aims to investigate novel pathways how the expression and activity of glyoxalase-1 are regulated. This interdisciplinary project expects to generate new understanding by combining relevant cell and animal models, protein chemistry, epi ....Augmenting the activity of glyoxalase-1 to increase dicarbonyl clearance . Reactive intermediates generated during our metabolism contribute to ageing. Glyoxalase-1 is a key defence enzyme against these toxic intermediates and therefore ageing itself. This project aims to investigate novel pathways how the expression and activity of glyoxalase-1 are regulated. This interdisciplinary project expects to generate new understanding by combining relevant cell and animal models, protein chemistry, epigenetics and structural biology. It is expected that this work will improve understanding of this fundamental biological defence. This will allow us to identify the potential means to enhance the capacity of glyoxalase-1 to the future benefit of biological ageing.Read moreRead less
Manipulation of mitochondrial function by Legionella pneumophila. . The intracellular bacterial pathogen Legionella pneumophila co-evolved with eukaryotic hosts and has developed sophisticated mechanisms to manipulate human cell function – mitochondria in particular – by secreting >300 effector proteins through a specialised Type-IV system into the host cell. This research aims to understand the function of effector proteins targeted to mitochondria; delivering important new knowledge in host-pa ....Manipulation of mitochondrial function by Legionella pneumophila. . The intracellular bacterial pathogen Legionella pneumophila co-evolved with eukaryotic hosts and has developed sophisticated mechanisms to manipulate human cell function – mitochondria in particular – by secreting >300 effector proteins through a specialised Type-IV system into the host cell. This research aims to understand the function of effector proteins targeted to mitochondria; delivering important new knowledge in host-pathogen and mitochondrial biology and advanced cell biology tools. With most of the effector proteins yet to be characterised, benefits from the project will be to reveal specifically how these target mitochondria, and more broadly, how bacterial pathogens manipulate organelles for their survival.Read moreRead less
How do apicomplexan parasites steal amino acids from their hosts? The single-celled parasites that cause malaria and toxoplasmosis are adept at stealing nutrients from the host animals that they infect. How they do this is, however, poorly understood. This project seeks to identify the processes by which these parasites scavenge amino acids, an essential class of nutrient, from their hosts. Using innovative experimental approaches, the project aims to identify and characterise the parasite prote ....How do apicomplexan parasites steal amino acids from their hosts? The single-celled parasites that cause malaria and toxoplasmosis are adept at stealing nutrients from the host animals that they infect. How they do this is, however, poorly understood. This project seeks to identify the processes by which these parasites scavenge amino acids, an essential class of nutrient, from their hosts. Using innovative experimental approaches, the project aims to identify and characterise the parasite proteins that mediate the uptake of different amino acids into the parasite. The intended outcomes of the project are to provide comprehensive insights into a fundamental aspect of parasite biology, and inform strategies to treat the diseases caused by these parasites by cutting off their nutrient supply.Read moreRead less
EFR3: Novel gatekeeper of cell proliferation. This interdisciplinary, cross-institutional project uses leading-edge mass spectrometry and the yeast genetic model to enhance knowledge of fundamental signalling mechanisms common to cell proliferation of eukaryotic cells. Building on extensive preliminary data that identifies novel energy-stress control points, this research will generate insights into critical and conserved features of nutrient stress control of cell proliferation that ensures cel ....EFR3: Novel gatekeeper of cell proliferation. This interdisciplinary, cross-institutional project uses leading-edge mass spectrometry and the yeast genetic model to enhance knowledge of fundamental signalling mechanisms common to cell proliferation of eukaryotic cells. Building on extensive preliminary data that identifies novel energy-stress control points, this research will generate insights into critical and conserved features of nutrient stress control of cell proliferation that ensures cell survival. This project advances basic and applied biology. Its outcomes will be relevant to several research areas and industries, specifically to the propagation of cell cultures that nowadays contributes to the production of a myriad of biotechnical and pharmaceutical commodities.
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