Structural And Functional Analysis Of A Cancer-linked Co-regulator Complex
Funder
National Health and Medical Research Council
Funding Amount
$729,571.00
Summary
We seek to understand the mechanisms by which genes are switched on and off throughout our lifetime. A number of multi-component protein machines are involved in this process but their make-up and mechanism of action is not understood. We will investigate the structure and function of one of these machines that has been strongly linked to cancer.
Platelet Glycoprotein Proteolysis: Novel Mechanisms And Risk Factors
Funder
National Health and Medical Research Council
Funding Amount
$441,473.00
Summary
Platelets are the richest source of amyloid precursor protein (APP) in the body. Platelet ADAM10 regulates both the expression and function of the major platelet collagen receptor GPVI, and protective APP processing. Coagulation protein Factor X has a role in activation of ADAM10. This activation is disrupted in blood that has been treated with direct oral anticoagulant (DOAC) rivaroxaban. This grant will investigate the implications for people taking rivaroxaban on regulation of APP and GPVI.
Role Of Transition Metal Ions And Redox Activity In The Development Of Atherosclerotic Plaques
Funder
National Health and Medical Research Council
Funding Amount
$196,018.00
Summary
Metal ions such as iron and copper have been reproted to be present in the lesions present in diseased human arteries and it has been suggested that these metal ions contribute to the development of atherosclerosis (hardening of the arteries) via their ability to catalyse the formation of highly reactive molecualr fragments called free radicals. Though metal ions are known to catalyse such reactions in test-tube experiments, both the presence of metal ions in diseased arteries and their ability ....Metal ions such as iron and copper have been reproted to be present in the lesions present in diseased human arteries and it has been suggested that these metal ions contribute to the development of atherosclerosis (hardening of the arteries) via their ability to catalyse the formation of highly reactive molecualr fragments called free radicals. Though metal ions are known to catalyse such reactions in test-tube experiments, both the presence of metal ions in diseased arteries and their ability to generate free radicals is controversial. This study will employ a novel, minimally-invasive, technique to assess the nature and quantity of metal ions present in well-defined human and animal lesions at different stages of lesion development. The ability of these metal ions to catalyse free radical formation from components present in the artery wall will also be assessed. The release of these metal ions from the artery wall to added organic molecules will be assessed as this might minimise their potential to cause damage, and provide a possible therapeutic strategy. These studies will therefore provide valuable information as to the significance and role of reactive metal ions in the development of human artery disease and the possible prevention, or minimisation, of such processes.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
Pathogen recognition and plant-defence activation by a novel Fusarium wilt-resistance protein from tomato. The devastating effects of Fusarium wilt disease of tomato is a threat to one of Australia's most economically important horticultural crops. Resistant tomato varieties offer the most effective means of control but the fundamental mechanisms underlying this resistance are yet to be understood. This research will increase our understanding of resistance to Fusarium wilt disease. The knowledg ....Pathogen recognition and plant-defence activation by a novel Fusarium wilt-resistance protein from tomato. The devastating effects of Fusarium wilt disease of tomato is a threat to one of Australia's most economically important horticultural crops. Resistant tomato varieties offer the most effective means of control but the fundamental mechanisms underlying this resistance are yet to be understood. This research will increase our understanding of resistance to Fusarium wilt disease. The knowledge gained will assist in the development of new robust, sustainable approaches to disease control, as well as the development of pre-emptive strategies to avert major outbreaks, which will ensure reliable productivity and minimal economic losses into the future.Read moreRead less
Translocation of secreted effector proteins from fungal pathogens into host plant cells. Every year, fungal diseases of plants cause huge losses in agricultural productivity and extensive environmental damage in Australia. Disease control in major crops, like wheat, currently relies heavily on breeding for disease resistance. However, fungal pathogens continually adapt to overcome plant defences, necessitating identification of new sources of resistance. The research in this project will eluc ....Translocation of secreted effector proteins from fungal pathogens into host plant cells. Every year, fungal diseases of plants cause huge losses in agricultural productivity and extensive environmental damage in Australia. Disease control in major crops, like wheat, currently relies heavily on breeding for disease resistance. However, fungal pathogens continually adapt to overcome plant defences, necessitating identification of new sources of resistance. The research in this project will elucidate the molecular basis of a new aspect of the establishment of plant infection by fungi, and in so doing will provide new avenues for the development of novel disease resistance strategies, with relevance in particular to devastating cereal diseases like wheat rust.Read moreRead less
Role of fungal secreted proteins as plant disease effectors. Many crop diseases are economically significant threats to agricultural productivity in Australia, with rust fungi in particular being a major problem for cereal grain production. Current methods of rust disease control are based on breeding for resistance but continued adaption by rust fungi to overcome plant defences means there is an urgent need for new methods of crop protection. This project will investigate molecular processes ....Role of fungal secreted proteins as plant disease effectors. Many crop diseases are economically significant threats to agricultural productivity in Australia, with rust fungi in particular being a major problem for cereal grain production. Current methods of rust disease control are based on breeding for resistance but continued adaption by rust fungi to overcome plant defences means there is an urgent need for new methods of crop protection. This project will investigate molecular processes underlying fungal infection of plants, focusing on mechanisms that enable fungi to take over the metabolism of infected cells. The research will provide basic knowledge for development of novel and durable disease resistance strategies.Read moreRead less
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE180100157
Funder
Australian Research Council
Funding Amount
$600,000.00
Summary
Confocal and single molecule microscopes for systems microscopy. This project aims to establish Australia’s first system microscopy facility with dedicated live-cell confocal and single-molecule fluorescence microscopes. In systems microscopy, the imaging workflow is automated so that large and unbiased data sets of the spatiotemporal organisation of molecules and cells can be generated. Combined with statistical and bioinformatics analyses, image-derived data provides system-wide information th ....Confocal and single molecule microscopes for systems microscopy. This project aims to establish Australia’s first system microscopy facility with dedicated live-cell confocal and single-molecule fluorescence microscopes. In systems microscopy, the imaging workflow is automated so that large and unbiased data sets of the spatiotemporal organisation of molecules and cells can be generated. Combined with statistical and bioinformatics analyses, image-derived data provides system-wide information that is not easily obtainable with other approaches. The project will enable Australian researchers to image and analyse the full complexity of biological systems, potentially transforming cell biology, drug development and understanding the molecular basis of disease. It will also demonstrate how the capacity of microscopy facilities can be enhanced and bias in imaging data reduced by automating data acquisition and mining of image-based data.Read moreRead less
Plant immunity to fungal and bacterial pathogens. Since 2003, the Australian wheat crop has been threatened by a continuing stripe rust epidemic, which has required an additional production expense of at least $100 million per annum in fungicides. This Australian National University (ANU) - Commonwealth Scientific and Industrial Research Organisation (CSIRO) joint proposal aims to exploit the next-generation genome sequencing and associated bioinformatic and proteomic methods which are poised to ....Plant immunity to fungal and bacterial pathogens. Since 2003, the Australian wheat crop has been threatened by a continuing stripe rust epidemic, which has required an additional production expense of at least $100 million per annum in fungicides. This Australian National University (ANU) - Commonwealth Scientific and Industrial Research Organisation (CSIRO) joint proposal aims to exploit the next-generation genome sequencing and associated bioinformatic and proteomic methods which are poised to revolutionise biology to investigate the wheat-fungus interaction. We will develop new effective approaches for environmentally benign stripe rust control based on new knowledge about how this fungus causes disease and avoids the wheat's immune surveillance system.Read moreRead less