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
AusDiab 3: Emerging Risk Factors For And Long-term Incidence Of Cardio-metabolic Diseases
Funder
National Health and Medical Research Council
Funding Amount
$2,616,397.00
Summary
This study will track 11,000 Australian adults over 12 years to determine how many develop diabetes, obesity, kidney and heart disease. The study will develop ways to best predict those who are going to develop these conditions before they have arisen, and will explore a range of novel risk factors to better understand these conditions.
Ascorbate and glutathione integrate the control of grapevine development. This project aims to make a step-change in understanding how the growth of woody perennial crops is regulated. The study of herbaceous annual plants has established that the antioxidants, ascorbate and glutathione, are important in regulating every step of plant development. However, this cannot readily translate to perennial life cycles. This project will develop novel genetic tools in grapevine that enable functional stu ....Ascorbate and glutathione integrate the control of grapevine development. This project aims to make a step-change in understanding how the growth of woody perennial crops is regulated. The study of herbaceous annual plants has established that the antioxidants, ascorbate and glutathione, are important in regulating every step of plant development. However, this cannot readily translate to perennial life cycles. This project will develop novel genetic tools in grapevine that enable functional studies of these antioxidants in a perennial plant for the first time. It will investigate how ascorbate and glutathione regulate the development of grapevine, and how these functions integrate with hormone and energy metabolism. The outcomes will advance our ability to manage perennial crops in current and future climates.Read moreRead less
The Role Of Capsid Protein Nucleolar Localisation In Chikungunya Virus: Implications For Vaccine Development
Funder
National Health and Medical Research Council
Funding Amount
$520,520.00
Summary
Chikungunya virus (CHIKV) is a globally widespread mosquito-borne alphavirus capable of causing considerable human morbidity and mortality. With no CHIKV vaccine or antiviral available this proposal aims to develop a live attenuated CHIKV vaccine, rationally designed by investigating the host cell nucleolar trafficking of CHIKV capsid protein. This vaccine has the potential to provide cross-protection against additional arthritogenic alphaviruses endemic to Australia such as Ross River virus.
Understanding and preventing workforce vulnerabilities in midlife and beyond. This project brings together frontline service agencies with researchers from two universities to study involuntary non-participation and under-participation in the labour market by midlife Australians. Quantitative and qualitative approaches will be used to understand pathways and outcomes so as to inform policy and practice responses.
Unlocking secrets of fertility restoration for hybrid breeding in crops. Hybrid varieties give higher and more stable yields than conventional lines, but a cost-effective system to make hybrid seed on a commercial scale is still missing for economically important crops like wheat or barley. By elucidating the mode of action of a new type of restorer gene plus exploiting ancient or exotic wheat and barley collections this project will reveal aspects of largely understudied mechanisms underlying f ....Unlocking secrets of fertility restoration for hybrid breeding in crops. Hybrid varieties give higher and more stable yields than conventional lines, but a cost-effective system to make hybrid seed on a commercial scale is still missing for economically important crops like wheat or barley. By elucidating the mode of action of a new type of restorer gene plus exploiting ancient or exotic wheat and barley collections this project will reveal aspects of largely understudied mechanisms underlying fertility restoration in wheat and barley. The expected outcomes of the proposed research have the potential to deliver new tools for hybrid seed production programs in wheat and barley. Higher and more stable yields from hybrids will ensure food security in the face of an uncertain climate and growing human population.Read moreRead less
ARC Centre of Excellence for Children and Families over the Life Course. New solutions are needed to underpin the Australian social ideal of a fair go, and to drive future global economic productivity. The Australian Productivity Commission identifies deep and persistent disadvantage as a significant problem in Australia given the failure of growing national prosperity over the past two decades to benefit underprivileged Australians. Social disadvantage is a global challenge. This Centre will ad ....ARC Centre of Excellence for Children and Families over the Life Course. New solutions are needed to underpin the Australian social ideal of a fair go, and to drive future global economic productivity. The Australian Productivity Commission identifies deep and persistent disadvantage as a significant problem in Australia given the failure of growing national prosperity over the past two decades to benefit underprivileged Australians. Social disadvantage is a global challenge. This Centre will advance basic, applied and translational research to reduce intergenerational and long-term disadvantage. Through the maturation of longitudinal datasets and advanced data integration we can follow the journeys of Australian families over generations and across the life course. This data will provide evidence for new policies and make a real difference to the lives of children and families.Read moreRead less
Novel Insights Into The Pathobiology Of Alphavirus Infections
Funder
National Health and Medical Research Council
Funding Amount
$827,660.00
Summary
Infections with mosquito-borne viruses are increasing at an alarming rate worldwide. Ross River virus is endemic in parts of Australia, PNG and Pacific islands, while chikungunya virus is distributed globally and causes recurrent pandemics that involve millions of people. These viruses cause severe musculoskeletal disease for several months after infection. This project aims to establish how these viruses interact with the human host to cause disease and may provide a basis for new treatments.
Mitochondrial Iron Overload And Friedreich's Ataxia: The Role Of Frataxin In Iron And Haem Metabolism
Funder
National Health and Medical Research Council
Funding Amount
$285,990.00
Summary
Friedreich's ataxia (FA) is due to the lack of a protein known as frataxin. Recent studies using Baker's yeast have shown that the deletion of frataxin results in the accumulation of toxic iron in the mitochondrion. More recently, a variety of studies have shown that FA patients have iron loading within their cells. The iron build-up may cause severe damage. At present, the role of frataxin in mammalian mitochondrial iron metabolism is unknown. Our preliminary studies demonstrate that frataxin i ....Friedreich's ataxia (FA) is due to the lack of a protein known as frataxin. Recent studies using Baker's yeast have shown that the deletion of frataxin results in the accumulation of toxic iron in the mitochondrion. More recently, a variety of studies have shown that FA patients have iron loading within their cells. The iron build-up may cause severe damage. At present, the role of frataxin in mammalian mitochondrial iron metabolism is unknown. Our preliminary studies demonstrate that frataxin is down-regulated by either erythroid differentiation or the haem precursor protoporphyrin IX (Becker and Richardson, submitted). These data strongly suggest a role for frataxin in iron metabolism. In the present study we will continue to assess if frataxin plays a role in the way cells handle iron. Using a unique model of mitochondrial iron overload developed in my lab (Richardson et al. (1996) BLOOD 87:3477), we will extensively investigate the iron metabolism of the mitochondrion in order to determine the function of frataxin and its role in Friedreich's ataxia. In addition, we have developed a series of new drugs known as iron chelators that can enter the mitochondrion due to their high lipid solubility (Becker and Richardson 1999 J. Lab. Clin. Med. 134:510). These latter drugs are far more effective than the chelator currently used to treat iron overload, desferrioxamine (DFO). Indeed, our chelators have been designed to result in high iron chelation efficacy but low toxicity (see Becker and Richardson, 1999). This exciting research may be crucial in understanding the development of FA and in creating new therapies such as the use of iron chelators.Read moreRead less
Mitochondrial Iron Overload And Friedreich's Ataxia: The Role Of Frataxin In Iron And Haem Metabolism
Funder
National Health and Medical Research Council
Funding Amount
$606,000.00
Summary
Friedreich's ataxia (FA) is due to the lack of a protein known as frataxin. A variety of studies using Baker's yeast and conditional frataxin knockout (KO) mice have shown that deletion of frataxin leads to the accumulation of toxic iron in their mitochondrion. More recently, a variety of studies have shown that FA patients have iron-loading within their mitochondrion. Iron in the highly redox active environment of the mitochondrion could contribute to the generation of cytotoxic radicals that c ....Friedreich's ataxia (FA) is due to the lack of a protein known as frataxin. A variety of studies using Baker's yeast and conditional frataxin knockout (KO) mice have shown that deletion of frataxin leads to the accumulation of toxic iron in their mitochondrion. More recently, a variety of studies have shown that FA patients have iron-loading within their mitochondrion. Iron in the highly redox active environment of the mitochondrion could contribute to the generation of cytotoxic radicals that cause severe damage. Further, cells deficient in frataxin are sensitive to oxidant stress and Fe chelators rescue oxidant-mediated death of cells from FA patients. Indeed, free radical scavengers have shown to be of use in the treatment of this disease. Studies in DR's lab during this NHMRC grant have shown that frataxin is down-regulated by erythroid differentiation or the haem precursor, protoporphyrin IX (BLOOD 2002;99:3813-22). These data indicate a role for frataxin in Fe metabolism and the pathogenesis of FA. In this study we will continue to examine the role of frataxin in the way cells handle Fe using experimental models developed under the current NHMRC grant. These include transfected cell lines with low frataxin expression generated using an expression vector containing anti-sense frataxin cDNA. Further we obtained the frataxin conditional KO mouse and generated a breeding colony. These animals display many of the pathological features of FA and are the best current model of the disease. Indeed, they will be critical for assessing the role of frataxin in Fe metabolism and as a model to test the ability of Fe-binding drugs to prevent the pathology observed. We designed lipid-soluble chelators that can enter the mitochondrion to bind Fe (Biochim Biophys Acta 2001;1536:133-140) and these ligands will be tested to prevent disease progression in the KO mice. This exciting research is crucial for understanding the pathogenesis of FA and in creating new therapies.Read moreRead less