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
Neurovascular pericytes in development and brain regeneration. The brain is responsible for a quarter of the body’s metabolism and is thus perfused by an extensive network of blood vessels. Pericytes surround these vessels and interact with neurons, glia, immune cells and neural stem cells of the neurovascular unit. Pericytes influence brain development, function and regeneration but remain enigmatic. This project investigates molecular control of pericyte development, functional coupling of per ....Neurovascular pericytes in development and brain regeneration. The brain is responsible for a quarter of the body’s metabolism and is thus perfused by an extensive network of blood vessels. Pericytes surround these vessels and interact with neurons, glia, immune cells and neural stem cells of the neurovascular unit. Pericytes influence brain development, function and regeneration but remain enigmatic. This project investigates molecular control of pericyte development, functional coupling of pericytes with adjacent cells and pericyte function in tissue regeneration. We aim to produce new fundamental knowledge in brain development, structure, function and evolution. New knowledge generated here may lead to future approaches in stem cell biology, tissue engineering, regeneration and ageing of the brain. Read moreRead less
Defining the origin of a cell lineage that surrounds and cleans the brain . The vertebrate brain is responsible for up to a quarter of the body’s metabolism, a metabolic load that produces large amounts of tissue waste and requires an efficient cleaning system. A recent discovery in zebrafish and preliminary data has uncovered a cell type surrounding the brain that derives from vasculature. These cells play fundamental roles in scavenging and clearing tissue wastes. The project aims to investiga ....Defining the origin of a cell lineage that surrounds and cleans the brain . The vertebrate brain is responsible for up to a quarter of the body’s metabolism, a metabolic load that produces large amounts of tissue waste and requires an efficient cleaning system. A recent discovery in zebrafish and preliminary data has uncovered a cell type surrounding the brain that derives from vasculature. These cells play fundamental roles in scavenging and clearing tissue wastes. The project aims to investigate the origins and control of this cell type in zebrafish and mouse brains. This will produce new knowledge in brain development, cellular composition, structure, function and evolution. Outcomes are expected to generate new approaches in stem cell biology, tissue engineering, regeneration and ageing of the brain.Read moreRead less
Mouse models for the identification of factors involved in muscle adaptation. The ability of muscle to adapt to meet functional demands is essential for mobility in normal daily life, in ageing well, in individuals with muscle diseases and nerve damage and in athletes. The ability of muscle to change its cellular composition is desirable for the livestock industry. Knowledge of how genes in muscle cells are regulated to adapt to demands has significant implications for public health and economic ....Mouse models for the identification of factors involved in muscle adaptation. The ability of muscle to adapt to meet functional demands is essential for mobility in normal daily life, in ageing well, in individuals with muscle diseases and nerve damage and in athletes. The ability of muscle to change its cellular composition is desirable for the livestock industry. Knowledge of how genes in muscle cells are regulated to adapt to demands has significant implications for public health and economic benefits. We have devised model systems that will allow us to identify the regulators of these genes in order to develop therapies to combat these changes in ageing and damaged muscle, to improve the quality of meat and optimise sport performance.Read moreRead less
Discovery of pathways to embryogenesis in pathogenic flatworm parasites using microdissection and transcriptomic technologies. The cost to Australia of flatworm parasites to animal production and human health is substantial (hundreds of millions of dollars per year). This research will give new insights into how flatworms reproduce and equip their progeny for survival, providing impetus for new vaccine or drug therapies to be developed. As these pathogens are more significant in Australia's ne ....Discovery of pathways to embryogenesis in pathogenic flatworm parasites using microdissection and transcriptomic technologies. The cost to Australia of flatworm parasites to animal production and human health is substantial (hundreds of millions of dollars per year). This research will give new insights into how flatworms reproduce and equip their progeny for survival, providing impetus for new vaccine or drug therapies to be developed. As these pathogens are more significant in Australia's near neighbours, this project will strengthen Australia's international leadership in this field. Our study will provide, for the first time for any helminth parasite, a freely available genetic database that profiles the gene expression repertoire of individual parasite tissues, a development likely to enhance the international effort in controlling these harmful diseases.Read moreRead less
Novel roles for importin alpha proteins in the nucleus. The project will provide fundamental new information about how changes in cell function are influenced by importin (IMP) alpha proteins, both through changes in gene transcription and through alterations to intracellular transport. These findings will inform areas of national priority that include Aging Well, Aging Productively with specific regard to cellular stress responses, and A Healthy Start to Life in the context of production of hea ....Novel roles for importin alpha proteins in the nucleus. The project will provide fundamental new information about how changes in cell function are influenced by importin (IMP) alpha proteins, both through changes in gene transcription and through alterations to intracellular transport. These findings will inform areas of national priority that include Aging Well, Aging Productively with specific regard to cellular stress responses, and A Healthy Start to Life in the context of production of healthy, genetically intact sperm. This project draws together an international team to investigate a phenomenon with implications for new understanding of normal developmental processes and the response of cells/tissues to disease conditions.Read moreRead less
Bipolar affective disorder (BP), or manic-depressive illness, is a major cause of disability and mortality worldwide. It has a lifetime prevalence of about 1% and suicide risk of about 20%. The disorder is characterised by episodes of mania or hypomania and depression, appearing in varying succession, with or without intermission. Twin, family, and adoptive studies point to a strong genetic component leading to the development of bipolar disorder, with a heritability of the order of 80%. Yet the ....Bipolar affective disorder (BP), or manic-depressive illness, is a major cause of disability and mortality worldwide. It has a lifetime prevalence of about 1% and suicide risk of about 20%. The disorder is characterised by episodes of mania or hypomania and depression, appearing in varying succession, with or without intermission. Twin, family, and adoptive studies point to a strong genetic component leading to the development of bipolar disorder, with a heritability of the order of 80%. Yet the identification of the genetic basis of the disease has proved exceedingly difficult, with numerous studies producing no definitive data. The lack of convincing results has been interpreted as an indication of complex genetic mechanisms and underlying differences between affected families and ethnic groups. Genetically isolated populations, where most individuals descend from a small number of founders, are believed to hold great potential for understanding the genetic basis of complex diseases, such as bipolar disorder. Affected subjects in such populations are likely to share the same predisposing genes, making these genes easier to identify. During the last 10 years, we have been involved in the study of bipolar disorder in one such population, with very promising results. In this project, we propose to take the research further by collecting more affected families, confirming the current positive findings and narrowing down the search to a small region, possibly a single gene. If successful, the study will be a major breakthrough which, by identifying a molecular pathway and disease mechanism, will contribute valuable and generally valid information on the biological basis of mood disorders.Read moreRead less
Identifying Novel Genes Causing Cytochrome C Oxidase (COX) Deficiency
Funder
National Health and Medical Research Council
Funding Amount
$426,917.00
Summary
Our bodies convert food into energy in tiny cellular power plants called mitochondria. Each year about 50 Australian children inherit disorders of mitochondrial energy generation. The most severe disorders cause infant death, while others cause degenerative diseases in later life, particularly affecting brain and muscle. In most cases we lack effective treatments. The genetic causes of mitochondrial disorders are incredibly diverse, with over 70 disease genes known. Some are located on the uniqu ....Our bodies convert food into energy in tiny cellular power plants called mitochondria. Each year about 50 Australian children inherit disorders of mitochondrial energy generation. The most severe disorders cause infant death, while others cause degenerative diseases in later life, particularly affecting brain and muscle. In most cases we lack effective treatments. The genetic causes of mitochondrial disorders are incredibly diverse, with over 70 disease genes known. Some are located on the unique mitochondrial DNA we inherit only from our mothers. Many more genes await discovery. This study focuses on the mitochondrial disorder cytochrome c oxidase (COX) deficiency, for which we have diagnosed 80 Australian patients. COX requires 13 separate components to be assembled together in order to work properly, but mutations in the genes encoding these components are not present in most patients. We believe that the most common problems will be in genes involved in assembling the components rather than in the components themselves. We will use a number of methods to pinpoint where in the genome the disease genes are located. A key to our strategy is identifying patients likely to have mutations in the same gene. We have identified two such groups, and will do studies that involving fusing two cell lines together to confirm they have the same disorder. We will then perform genetic mapping to look for regions of similarity in the genome using DNA (SNP) chips. We will test how well the genes in such regions are expressed, whether we can correct the problem in cultured skin cells by introducing a healthy copy of that chromosome, and look for gene mutations. Identifying these genes will allow us to improve future diagnosis and prevention and may allow us to develop new methods of treatment. Milder mitochondrial problems also contribute to a range of more common diseases such as diabetes and Alzheimer disease, so any new treatments could potentially have wide applicationRead moreRead less
The role of short tandem repeat DNA variation in the evolution of human psychological diversity. The proposed work addresses fundamental questions about human nature. It ties together the evolutionary processes that have shaped us as a species with the way our genes influence: our personalities, the way we think and how we behave. It introduces a novel approach to addressing questions about the role of genetics in human variation that will contribute substantially to the way we understand, perce ....The role of short tandem repeat DNA variation in the evolution of human psychological diversity. The proposed work addresses fundamental questions about human nature. It ties together the evolutionary processes that have shaped us as a species with the way our genes influence: our personalities, the way we think and how we behave. It introduces a novel approach to addressing questions about the role of genetics in human variation that will contribute substantially to the way we understand, perceive and manage important aspects of human diversity.Read moreRead less