A New Model For The Pathogenesis Of Rheumatic Fever: Superantigen Priming Of The Immune Response To Group A Streptococci
Funder
National Health and Medical Research Council
Funding Amount
$248,820.00
Summary
Acute rheumatic fever (ARF) is now rare in developed countries. However, it remains a major problem in Aboriginal Australians in the NT where the rate of ARF is the highest in the world. This leads to high rates of rheumatic heart disease (up to 3% of individuals in some communities) and a premature mortality of over four times that for developing countries. Immunisation and improved living conditions offer a long-term solution but these remain a distant prospect. In the short and medium term, c ....Acute rheumatic fever (ARF) is now rare in developed countries. However, it remains a major problem in Aboriginal Australians in the NT where the rate of ARF is the highest in the world. This leads to high rates of rheumatic heart disease (up to 3% of individuals in some communities) and a premature mortality of over four times that for developing countries. Immunisation and improved living conditions offer a long-term solution but these remain a distant prospect. In the short and medium term, control of this ARF will partly depend on new and better treatment and prevention strategies. To achieve these goals a deeper understanding of the immune mechanisms underlying this disease is urgently needed. It is known that ARF is caused by an abnormal immune response following streptococcal infection. This leads to the production of cells called T cells that attack the body s own tissues rather than the bacteria itself. This autoimmune disease is responsible for the heart damage that underlies ARF. It is believed that this proces only occurs when susceptible individuals are infected with specific rheumatogenic strains of streptococci. However there are a number of deficiencies in this model and it is proposed that there is an additional factor responsible for the abnormal immune response in ARF. This project will explore the possibility that bacterial toxins called superantigens are the critical missing factor , by studying the immune response in ARF. Superantigens are produced by certain streptococci and staphylococci, and are potent in minute quantities causing widespread activation of the immune system. They have been found to play an important role in a number of autoimmune diseases and the type of immune response found in ARF fits well with that expected if superantigens were involved. If superantigens play an important role in causing the abnormal immune response in ARF then a number of new avenues would open for the treatment and prevention of this disease.Read moreRead less
Discovery Early Career Researcher Award - Grant ID: DE180100306
Funder
Australian Research Council
Funding Amount
$365,058.00
Summary
Does spurious maternal-fetal signalling support the evolution of a placenta. This project aims to test a model that explains how the placenta has evolved as a new organ more than 100 times in fishes, reptiles, and mammals including our own ancestors. The project will assess whether regulatory components of the placenta evolve as a result of spurious maternal-fetal signalling following egg retention and eggshell loss in viviparous reptiles. Expected outcomes of this project include a new understa ....Does spurious maternal-fetal signalling support the evolution of a placenta. This project aims to test a model that explains how the placenta has evolved as a new organ more than 100 times in fishes, reptiles, and mammals including our own ancestors. The project will assess whether regulatory components of the placenta evolve as a result of spurious maternal-fetal signalling following egg retention and eggshell loss in viviparous reptiles. Expected outcomes of this project include a new understanding of how complex organs originate and evolve in animals. This will benefit society through a broader depth of understanding of our own evolutionary history and provides a framework for future studies to investigate the origin and evolution of organs more broadly in animals.Read moreRead less
The evolution of female resistance to male reproductive traits in animals. Australia has an outstanding international reputation in the fields of Ecology and Evolution. This study will reinforce Australia's excellence in these fields. Sexual conflict is a topic of great scientific interest because it has important implications for evolutionary theory and our understanding of the diverse strategies that animals use to attract or repel potential mates. Consequently, articles on this topic feature ....The evolution of female resistance to male reproductive traits in animals. Australia has an outstanding international reputation in the fields of Ecology and Evolution. This study will reinforce Australia's excellence in these fields. Sexual conflict is a topic of great scientific interest because it has important implications for evolutionary theory and our understanding of the diverse strategies that animals use to attract or repel potential mates. Consequently, articles on this topic feature regularly in top international scientific journals. In addition, research on the unique social behaviours of Australian animals holds general public interest and plays an important role in attracting young people to careers in science. Read moreRead less
Inflammation as an early form of maternal-fetal signalling in pregnancy. The project aims to understand the role of inflammatory signalling in marsupial pregnancy. This project is expected to explain why inflammation, a processes normally confined to injury and infection, is a part of reproduction in live-bearing mammals. Outcomes of this project include robust measures of the capacity for, impact of, and evolution of, inflammatory signalling in marsupial pregnancy. The project will provide new ....Inflammation as an early form of maternal-fetal signalling in pregnancy. The project aims to understand the role of inflammatory signalling in marsupial pregnancy. This project is expected to explain why inflammation, a processes normally confined to injury and infection, is a part of reproduction in live-bearing mammals. Outcomes of this project include robust measures of the capacity for, impact of, and evolution of, inflammatory signalling in marsupial pregnancy. The project will provide new knowledge about the unique biology of Australia's marsupial fauna.This project will provide significant benefits, including enhanced capacity for reproduction research in Australia, new international collaborations between Melbourne and Yale, and a new explanation for the puzzling role of inflammation in pregnancy.Read moreRead less
Old genes learning new tricks: characterising regulatory changes driving increased heart complexity during vertebrate evolution. The heart has dramatically increased in morphological complexity during vertebrate evolution but the molecular basis driving these major changes remains unknown. Using comparative genomics approaches, this project will explore changes in the regulation of genes involved in heart formation that lead to changes in cardiac structure. It will elucidate for the first time t ....Old genes learning new tricks: characterising regulatory changes driving increased heart complexity during vertebrate evolution. The heart has dramatically increased in morphological complexity during vertebrate evolution but the molecular basis driving these major changes remains unknown. Using comparative genomics approaches, this project will explore changes in the regulation of genes involved in heart formation that lead to changes in cardiac structure. It will elucidate for the first time the cardiac regulatory repertoire in zebrafish and will compare it with that of fly and mouse using cutting-edge bioinformatics pipelines. This work will unravel cardiac-specific regulatory modifications that give rise to evolutionary changes. On a broader scale, it will shed new light on the role of regulatory innovations over gene innovations in the emergence of new traits.Read moreRead less
Linkages between productivity and consistent behavioural traits in fish: implications for harvesting, climate impacts, and selective breeding for aquaculture. The extent to which behavior, growth and reproduction are genetically linked in fish populations is unknown, but critical for predicting the impacts of fish harvesting and climate warming, and developing fish stains for aquaculture. If strongly linked, fish harvest will always remove aggressive, large and productive fish, requiring their p ....Linkages between productivity and consistent behavioural traits in fish: implications for harvesting, climate impacts, and selective breeding for aquaculture. The extent to which behavior, growth and reproduction are genetically linked in fish populations is unknown, but critical for predicting the impacts of fish harvesting and climate warming, and developing fish stains for aquaculture. If strongly linked, fish harvest will always remove aggressive, large and productive fish, requiring their protection; in aquaculture, selecting for productive fish will also increase aggression-related injuries. If not strongly linked, we may be able to select for high productivity and low aggression in fish, or high productivity and low metabolism, thus reducing feed costs in aquaculture associated with aggressive behaviour leading to injury and infection, and reduced growth at warmer temperatures.Read moreRead less
The role of natural selection in macroevolution: a case study examining convergence of form and function in marine predator guilds. Darwin's theory of evolution natural selection is one of the most successful in the history of science and provides the framework for modern biology: however, areas of debate or uncertainty are often misinterpreted by non-scientists as indication of fundamental flaws in the theory. New 'hi-tech' tools provide the opportunity to re-examine these areas, and also to de ....The role of natural selection in macroevolution: a case study examining convergence of form and function in marine predator guilds. Darwin's theory of evolution natural selection is one of the most successful in the history of science and provides the framework for modern biology: however, areas of debate or uncertainty are often misinterpreted by non-scientists as indication of fundamental flaws in the theory. New 'hi-tech' tools provide the opportunity to re-examine these areas, and also to demonstrate the process of science to the public. The new tool is Computational Biomechanics, the future of studying biological form, and this project will further develop the leading role of Australian research in this technology which has applications for palaeontology, environmental management, medical science, and the next generation of engineering using 'biomaterials'.Read moreRead less
Molecular dissection of the functional regions of genes that encode actinins (ACTN2 and ACTN3) and their contribution to normal variation in skeletal muscle function. The project has discovered a common genetic variant that affects skeletal muscle structure, function and metabolism and influences athletic ability, and response to diet and exercise. The project will study how this gene influences muscle bulk and strength, the metabolic efficiency of muscle and the risk of obesity in the general ....Molecular dissection of the functional regions of genes that encode actinins (ACTN2 and ACTN3) and their contribution to normal variation in skeletal muscle function. The project has discovered a common genetic variant that affects skeletal muscle structure, function and metabolism and influences athletic ability, and response to diet and exercise. The project will study how this gene influences muscle bulk and strength, the metabolic efficiency of muscle and the risk of obesity in the general population.Read moreRead less
Evolution. Morphodynamics and History of the Younghusband Peninsula. This project will examine the history and evolution of the Sir Richard-Younghusband Peninsula (SRYP) complex barrier in SA. The aims are to derive a understanding of how the influences of relative sea-level changes, neotectonics, and sediment supply, can produce remarkably different responses in barrier development. No complex barrier (i.e. foredune ridges in one portion, transgressive dunefields in another) has ever been compr ....Evolution. Morphodynamics and History of the Younghusband Peninsula. This project will examine the history and evolution of the Sir Richard-Younghusband Peninsula (SRYP) complex barrier in SA. The aims are to derive a understanding of how the influences of relative sea-level changes, neotectonics, and sediment supply, can produce remarkably different responses in barrier development. No complex barrier (i.e. foredune ridges in one portion, transgressive dunefields in another) has ever been comprehensively drilled, dated, modelled, or examined in the context of indigenous occupation and oral histories in Australia. The study provides excellent analogues for barrier and dune response, and shoreline translation to varying rates of sea level rise, paralleling pressures facing all coastlines today.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