Diseases Of Aminoacid Transport: Genetic, Molecular And Biochemical Studies
Funder
National Health and Medical Research Council
Funding Amount
$394,173.00
Summary
Aminoacids are essential building blocks of all living things. They are taken up and retained in the body by highly specific pumps on the surface of cells. By understanding the mechanisms that control aminoacids, we will not only uncover pathways common to normal biology but also shed light on mechanisms of disease in humans. Specifically, the aminoacidurias include a number of inherited diseases of aminoacid transport that result in failure of uptake and retention of particular aminoacids. Hart ....Aminoacids are essential building blocks of all living things. They are taken up and retained in the body by highly specific pumps on the surface of cells. By understanding the mechanisms that control aminoacids, we will not only uncover pathways common to normal biology but also shed light on mechanisms of disease in humans. Specifically, the aminoacidurias include a number of inherited diseases of aminoacid transport that result in failure of uptake and retention of particular aminoacids. Hartnup disease is an inherited disorder of neutral aminoacid transport that can lead to a sun-sensitive skin rash, difficulties in controlling movements and walking and other neurological symptoms including mental retardation. A major feature of Hartnup disease is its clinical variability. We have recently identified the main genetic cause for Hartnup disease, and named the gene SLC6A19. We wish to examine whether the clinical variability observed is a consequence of genetic changes and variability in SLC6A19 and other possible genes. Two other aminoacidurias to be studied are dicarboxylic aminoaciduria and iminoglycinuria; both of which are also variable in their clinical consequences ranging from normality to mental retardation. Owing to the relative rarity of these disorders, we are fortunate to have exclusive access to individuals identified by the largest neonatal screening programme for aminoacidurias in the world, based in Canada, and other clinical cohorts within Australia. We will undertake genetic testing to localise and-or confirm the gene(s) involved in these diseases for the first time anywhere and then seek to explain their clinical variability based on functional analyses. We have established a team of researchers with complementary skills from three sites comprising the Australian Aminoaciduria Consortium. Outcomes from this project should impact on the causes and possible therapies for other important medical diseases including motor neurone disease.Read moreRead less
Sex-specific epigenetic atlas across lifespan . This project aims to uncover sex-specific molecular marks that either predict or mediate healthy ageing across multiple tissues in humans. This project expects to generate new knowledge of cellular heterogeneity and epigenetic control of phenotype and healthy ageing. Further, we anticipate to uncover age-associated changes that differ between males and females, an area of chronic research under representation. These outcomes will lead to a comprehe ....Sex-specific epigenetic atlas across lifespan . This project aims to uncover sex-specific molecular marks that either predict or mediate healthy ageing across multiple tissues in humans. This project expects to generate new knowledge of cellular heterogeneity and epigenetic control of phenotype and healthy ageing. Further, we anticipate to uncover age-associated changes that differ between males and females, an area of chronic research under representation. These outcomes will lead to a comprehensive understanding of fundamental biological processes across lifespan, and our development of an open access atlas will underpin evidence-based personalised health strategies to keep Australians healthier for longer. Read moreRead less
The molecular evolution of wings in flightless birds. The flightless Australian emu and New Zealand kiwi have small wings, while the extinct moa had none at all. This project will identify the genetic changes that have lead to wing reduction and loss in flightless birds. The results will shed light on the genetic control of forelimb development and how it has evolved.
Phasevarions of Haemophilus influenzae: mechanisms and origins of a novel epigenetic system controlling coordinated random switching in expression of multiple genes. Central to the utilisation of biological information is our ability to identify and interpret DNA sequence information from genomes. In bacteria that cause disease, these investigations can identify key aspects of the infectious process or potential components of vaccines or new targets for antibiotics. Our recent work has identifie ....Phasevarions of Haemophilus influenzae: mechanisms and origins of a novel epigenetic system controlling coordinated random switching in expression of multiple genes. Central to the utilisation of biological information is our ability to identify and interpret DNA sequence information from genomes. In bacteria that cause disease, these investigations can identify key aspects of the infectious process or potential components of vaccines or new targets for antibiotics. Our recent work has identified a new genetic system, the 'phasevarion', that mediates random expression of multiple genes. The proposed research aims to advance our understanding of gene expression at the most basic level, revealing how bacteria generate diverse populations to evade environmental and immune stresses, and facilitating improved interpretation and use of DNA sequences for researchers and industry in this field.Read moreRead less
The Epigenetics of Sex in the Dragon. Genetic codes do not directly translate to phenotypes -- environment acts through epigenetics to modify development. We use advanced molecular techniques to examine how epigenetics responds to temperature to reverse sex in our novel animal model, the dragon lizard. How does the cell sense temperature? Once the extrinsic signal is captured, how does it influence chromatin modification to release or suppress key genes in the sex differentiation pathway? Which ....The Epigenetics of Sex in the Dragon. Genetic codes do not directly translate to phenotypes -- environment acts through epigenetics to modify development. We use advanced molecular techniques to examine how epigenetics responds to temperature to reverse sex in our novel animal model, the dragon lizard. How does the cell sense temperature? Once the extrinsic signal is captured, how does it influence chromatin modification to release or suppress key genes in the sex differentiation pathway? Which sex genes are targets? Epigenetic enzymes are astonishingly conserved, providing exciting opportunities to draw from human systems to unravel novel signatures of temperature-induced sex switching in reptiles. This project will advance knowledge of developmental programming generally.Read moreRead less
The Evolution and Diversification of Apicomplexan Cell Invasion Mechanisms. Insights gained through this project, about the mechanisms of cell invasion in Apicomplexan parasites, will have far reaching implications for a number of parasites of great significance to humans and animals. Since host cell invasion is a key step in the parasite lifecycle, proteins identified here will be prime targets for novel drugs that prevent invasion or antigens that can be used as vaccines. This will be importan ....The Evolution and Diversification of Apicomplexan Cell Invasion Mechanisms. Insights gained through this project, about the mechanisms of cell invasion in Apicomplexan parasites, will have far reaching implications for a number of parasites of great significance to humans and animals. Since host cell invasion is a key step in the parasite lifecycle, proteins identified here will be prime targets for novel drugs that prevent invasion or antigens that can be used as vaccines. This will be important for developing new control strategies for diseases of global significance such as malaria or toxoplasmosis, as well as those of national importance to the food industry of Australia, including diseases like babesiosis and coccidiosis that cause significant economic loss to the livestock and poultry industries each year.Read moreRead less
Understanding the evolution of the alternation of generations in the land plant life cycle. This project will investigate the genetic basis and evolution of the land plant life cycle, in which both haploid and diploid phases consist of complex multicellular bodies. The project's findings, which will be made using two model laboratory plants, will be applicable to all plants and will help understand important processes such as pollen and seed production.
Elucidating the genetic basis of newly evolved metabolic functions in yeast. Elucidating the genetic basis of newly evolved metabolic functions in yeast. This project intends to research how complex metabolic pathways originate and evolve. This project will use cutting edge genome sequencing and molecular techniques to elucidate the heritable genetic basis of Baker’s yeast, which has been the selectively evolved to use xylose as a sole carbon source: something vital for second generation biofuel ....Elucidating the genetic basis of newly evolved metabolic functions in yeast. Elucidating the genetic basis of newly evolved metabolic functions in yeast. This project intends to research how complex metabolic pathways originate and evolve. This project will use cutting edge genome sequencing and molecular techniques to elucidate the heritable genetic basis of Baker’s yeast, which has been the selectively evolved to use xylose as a sole carbon source: something vital for second generation biofuel production that wild yeast cannot do. This project will combine detailed molecular characterisation of highly adapted yeast strains with a novel "molecular palaeontology" approach to trace the evolutionary process and identify functionally significant loci under selection. Detailed characterisation of this trait will accelerate the development of future yeast strains and test fundamental evolutionary theories.Read moreRead less
Molecular mechanisms that generate muscle cell type diversity. The general aim of this project is to exploit the advantages of the zebrafish system and our access to the embryology of Australian shark species to generate an understanding of the basis for muscle fibre diversity and evolution. While there is some understanding of the fundamental genetic basis of how to make an individual muscle cell from a nascent myoblast there is far less knowledge on how individual muscle cells generate mature ....Molecular mechanisms that generate muscle cell type diversity. The general aim of this project is to exploit the advantages of the zebrafish system and our access to the embryology of Australian shark species to generate an understanding of the basis for muscle fibre diversity and evolution. While there is some understanding of the fundamental genetic basis of how to make an individual muscle cell from a nascent myoblast there is far less knowledge on how individual muscle cells generate mature muscle types and patterns. The intended outcome of this research is to generate understanding of the complex molecular basis of muscle patterning in the simple paradigm of the zebrafish myotome that could be applied across the vertebrate phylogeny.Read moreRead less
Development and evolution of land plant shoots. How do plants grow and develop their wonderful diversity of forms, from cereal crops to eucalypt forests? The project aims to understand basic mechanisms of plant development via comparative studies using the model angiosperm, Arabidopsis, and the liverwort, Marchantia, which possesses a simplified genome. Comparative studies of the genetic basis of the body plan, branching, and hormonal action could unlock their evolutionary elaboration from the s ....Development and evolution of land plant shoots. How do plants grow and develop their wonderful diversity of forms, from cereal crops to eucalypt forests? The project aims to understand basic mechanisms of plant development via comparative studies using the model angiosperm, Arabidopsis, and the liverwort, Marchantia, which possesses a simplified genome. Comparative studies of the genetic basis of the body plan, branching, and hormonal action could unlock their evolutionary elaboration from the simpler liverworts to more complex flowering plants. The project may generate new understanding of the principles of how genes and hormones control the architecture of plant shoot systems, and support the targeted selection of new agricultural plants.Read moreRead less