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
Genetic control of plant organ growth. Plants organs, such as leaves and petals, have a distinct size and shape reflecting differences in growth. Despite its importance, very little is known about the mechanisms that regulate growth. The objectives of this proposal are a) to test whether organ growth depends on cell-cell signalling and b) to identifying genes that regulate growth, and to characterize their molecular function.
Marsupial germ cells and genes. Germ cells are the most fascinating cells in the body, since theirs is the unique responsibility for transmitting life from generation to generation. Studies in mice have suggested that position in the embryo determines their origin, but the early embryology of the mouse is so different from that of other mammals that the events need confirming and extending in another species. The simplified embryology of the tammar wallaby makes it ideal for studying one of the ....Marsupial germ cells and genes. Germ cells are the most fascinating cells in the body, since theirs is the unique responsibility for transmitting life from generation to generation. Studies in mice have suggested that position in the embryo determines their origin, but the early embryology of the mouse is so different from that of other mammals that the events need confirming and extending in another species. The simplified embryology of the tammar wallaby makes it ideal for studying one of the most fundamental questions in the whole of biology: what is the basis for the primal distinction between sex and soma?Read moreRead less
How does the unilaminar blastocyst form an embryo? Marsupials are synonymous with Australia and they are scientifically amazing. An understanding how the single-layered marsupial blastocyst cells are directed to form the complex organisation of an embryo would help us understand the biology underlying the developmental potential of all cells. Understanding these processes is not only of great fundamental interest to developmental biology but also for the development of embryonic stem cell lines. ....How does the unilaminar blastocyst form an embryo? Marsupials are synonymous with Australia and they are scientifically amazing. An understanding how the single-layered marsupial blastocyst cells are directed to form the complex organisation of an embryo would help us understand the biology underlying the developmental potential of all cells. Understanding these processes is not only of great fundamental interest to developmental biology but also for the development of embryonic stem cell lines. This research will continue Australia's high profile in reproductive biology using one of our iconic native mammals. A greater understanding of marsupial reproduction will also contribute to management of our threatened marsupial populations.Read moreRead less
Taming the intruders: the domestication of Tigger transposable elements in mammals. It has become apparent that most of the DNA that makes us what we are is actually comprised of the remnants of invading parasitic DNA acquired over time. A continual battle exists between host which tries to silence or remove this DNA, and the parasite that tries to multiply and spread. We are currently investigating an intriguing aspect of this process that involves host genomes 'domesticating' parasitic DNA to ....Taming the intruders: the domestication of Tigger transposable elements in mammals. It has become apparent that most of the DNA that makes us what we are is actually comprised of the remnants of invading parasitic DNA acquired over time. A continual battle exists between host which tries to silence or remove this DNA, and the parasite that tries to multiply and spread. We are currently investigating an intriguing aspect of this process that involves host genomes 'domesticating' parasitic DNA to provide novel functions, thereby facilitating the evolution of specific characteristics within species.Read moreRead less
Identification of nuclear reprogramming factors in oocyte cytoplasm. The mature oocyte contains dominant factors that are capable of erasing tissue specific gene expression profiles of somatic cells. These reprogramming factors would be valuable for dedifferentiation of cells and for nuclear transfer in animal cloning. The research involves determination of reprogramming factors present in active cytoplasm following enucleation of the germinal vesicle, blockage of transcription and translation, ....Identification of nuclear reprogramming factors in oocyte cytoplasm. The mature oocyte contains dominant factors that are capable of erasing tissue specific gene expression profiles of somatic cells. These reprogramming factors would be valuable for dedifferentiation of cells and for nuclear transfer in animal cloning. The research involves determination of reprogramming factors present in active cytoplasm following enucleation of the germinal vesicle, blockage of transcription and translation, and timed cultures. The assays will involve maintenance of reprogramming ability and erasure of somatic gene transcription. By subtractive elimination the function of isolated proteins which are involved in reprogramming will be identified for potential recombinant production.Read moreRead less
A role for Cited2, Transforming Growth Factor-beta and matrix metaloproteinases in trophoblast invasion and placenta formation. The placenta is essential for the growth and development of the fetus, and if it fails to form correctly during pregnancy, it can have dramatic effects that can result death in utero, or adult onset diseases. Our research aims to understand how one protein functions in placenta formation. We will also investigate how this protein works at the molecular level in a proces ....A role for Cited2, Transforming Growth Factor-beta and matrix metaloproteinases in trophoblast invasion and placenta formation. The placenta is essential for the growth and development of the fetus, and if it fails to form correctly during pregnancy, it can have dramatic effects that can result death in utero, or adult onset diseases. Our research aims to understand how one protein functions in placenta formation. We will also investigate how this protein works at the molecular level in a process that enables single cells to respond to molecules sent from a distance by other cells (TGF-beta signalling). This process is also very important for a host of other biological processes relevant to human health, including cancer.Read moreRead less
A bird's eye view of sex: the chicken embryo as a model for gonadal development. The development of an embryo as either male or female (sex determination) is a fundamental biological process that fascinates both scientific and lay communities alike. This project will use the chicken embryo as a unique model organism to study how genes control sex determination. We will bring a novel method to our field of study; the use of avian viruses to deliver genes into embryos. This project will enhance ou ....A bird's eye view of sex: the chicken embryo as a model for gonadal development. The development of an embryo as either male or female (sex determination) is a fundamental biological process that fascinates both scientific and lay communities alike. This project will use the chicken embryo as a unique model organism to study how genes control sex determination. We will bring a novel method to our field of study; the use of avian viruses to deliver genes into embryos. This project will enhance our understanding of a basic biological process. It will have application to the poultry industry, in terms of sex ratio manipulation. It will also aid in the diagnosis of humans born with sexual abnormalities. The project will consolidate Australia's standing as a world leader in the area of reproduction and development.Read moreRead less
Discovering mechanisms of primary embryonic tissue migration through live cell imaging and novel genetic approaches. The studies proposed here will provide concepts and knowledge about the molecular basis of cell migration that will impact on diverse aspects of human health, such as the causes and nature of tumour metastasis and our understanding of the developmental basis of birth defects. In addition, understanding cell migration mechanisms will allow us to better predict or control the behav ....Discovering mechanisms of primary embryonic tissue migration through live cell imaging and novel genetic approaches. The studies proposed here will provide concepts and knowledge about the molecular basis of cell migration that will impact on diverse aspects of human health, such as the causes and nature of tumour metastasis and our understanding of the developmental basis of birth defects. In addition, understanding cell migration mechanisms will allow us to better predict or control the behaviour of therapeutic stem cells introduced into the body.Read moreRead less
How does Fat cadherin control organ size in Drosophila, and cancer in humans? The primary function of Fat cadherin is to dictate the appropriate size of organs in developing animals. Deficiency in the fat gene results in vastly overgrown organs and can lead to the formation of cancer in humans. Our study will provide important insights into how the size of organs are controlled during development. Our research findings will have important implications for several aspects of human health and biol ....How does Fat cadherin control organ size in Drosophila, and cancer in humans? The primary function of Fat cadherin is to dictate the appropriate size of organs in developing animals. Deficiency in the fat gene results in vastly overgrown organs and can lead to the formation of cancer in humans. Our study will provide important insights into how the size of organs are controlled during development. Our research findings will have important implications for several aspects of human health and biology, and will increase our understanding of diseases that arise due to aberrant tissue growth, such as cancer. Our research findings will thus be of substantial national benefit, given that cancer is now the biggest cause of death in Australia, and that more than 88,000 Australians are diagnosed with cancer each year. Read moreRead less