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Fibrtic lung diseases are a major health burden, and are a leading causes of mortality and morbidity worldwide. These diseases are effectively incurable, and a considerable number eventually require lung transplants. As such these diseases are prime candidates for stem cell therapies to regenerate and repair the lung. However, the lack of knowledge about the precise identity, organisation and regulation of these cells; how to deliver them effectively to the damaged lung; and how to pre-condition ....Fibrtic lung diseases are a major health burden, and are a leading causes of mortality and morbidity worldwide. These diseases are effectively incurable, and a considerable number eventually require lung transplants. As such these diseases are prime candidates for stem cell therapies to regenerate and repair the lung. However, the lack of knowledge about the precise identity, organisation and regulation of these cells; how to deliver them effectively to the damaged lung; and how to pre-condition their site of lodgement to best harness their potential. This project aims to address these issues. We have recently identified a rare population of cells in the adult mouse lung which has a number of characteristics consistent with that of an adult stem cell. We are able to grow these cells in tissue culture, and we have preliminary data suggesting that they can regenerate lung tissue when transplanted. The aim of this project is to precisely identify these cells, develop methods for their isolation and determine their location in the lung. The assays we will develop in this model will then be used to identify stem cells in the bone marrow which have similar properties and which could potentially be used clinically to alleviate lung disease. The project brings together a group of investigators with unique expertise in the isolation and analysis of adult stem cells, and in clinical and experimental respiratory medicine to develop preclinical models in the mouse which are prerequisite for the developement and implementation of step cell based therapies for lung disease in humans.Read moreRead less
Mechanisms Of Nedd4/Nedd4-2-mediated Regulation Of The Epithelial Sodium Channel
Funder
National Health and Medical Research Council
Funding Amount
$471,000.00
Summary
The epithelial sodium channel (ENaC) is a highly specific ion channel expressed in the apical membrane of some tissues. In the kidney, ENaC activity is responsible for maintaining sodium balance, blood volume and blood pressure. In the lung ENaC function is required for fluid clearance. Abnormal regulation of ENaC is associated with conditions such as hypertension, cystic fibrosis and pulmonary oedema. Delineating the molecular basis of the regulation of ENaC is vital in understanding disease me ....The epithelial sodium channel (ENaC) is a highly specific ion channel expressed in the apical membrane of some tissues. In the kidney, ENaC activity is responsible for maintaining sodium balance, blood volume and blood pressure. In the lung ENaC function is required for fluid clearance. Abnormal regulation of ENaC is associated with conditions such as hypertension, cystic fibrosis and pulmonary oedema. Delineating the molecular basis of the regulation of ENaC is vital in understanding disease mechanisms and in defining targets for novel therapeutics for the treatment of disorders that arise due to sodium imbalance. Furthermore, ENaC and the molecules involved in the channel regulatory cascade are potential candidate genes in defining the genetic causes of human hypertension and salt wasting disorders. Previous studies from our laboratories and by other groups have shown that Nedd4 and Nedd4-2 proteins are key players in regulating ENaC activity. Our recent NHMRC supported work has identified another important protein, Grk2, as a regulator of ENaC. The work proposed in this application is an extension of our recent findings and will enable us to fully define how Nedd4-Nedd4-2 and Grk2 regulate the activity of ENaC.Read moreRead less
The regulation of skeletal muscle mass. This project aims to delineate a pathway involved in regulating skeletal muscle mass, and examine whether disrupting mitochondrial phospholipid synthesis affects mitochondrial structure and function, causing muscle wasting. Defining a new atrophy pathway will advance understanding of the mechanisms that control muscle mass. This project could have important economic and quality of life benefits, especially for agriculture, where achieving optimal muscle ma ....The regulation of skeletal muscle mass. This project aims to delineate a pathway involved in regulating skeletal muscle mass, and examine whether disrupting mitochondrial phospholipid synthesis affects mitochondrial structure and function, causing muscle wasting. Defining a new atrophy pathway will advance understanding of the mechanisms that control muscle mass. This project could have important economic and quality of life benefits, especially for agriculture, where achieving optimal muscle mass ensures international competitiveness, productivity and economic growth, and successful ageing, where maintaining muscle mass is essential.Read moreRead less
Selective secretion: a novel mechanism of protein trafficking and its role in Phytophthora pathogenicity. Agriculturally important crops and over 3,000 Australian native plants are susceptible to diseases caused by Phytophthora, fungus-like pathogens that live in the soil. Economic losses exceed $200m pa and natural ecosystems are being destroyed on a vast scale. Phytophthora control depends upon a limited number of chemical inhibitors to which resistance has already emerged. New control stra ....Selective secretion: a novel mechanism of protein trafficking and its role in Phytophthora pathogenicity. Agriculturally important crops and over 3,000 Australian native plants are susceptible to diseases caused by Phytophthora, fungus-like pathogens that live in the soil. Economic losses exceed $200m pa and natural ecosystems are being destroyed on a vast scale. Phytophthora control depends upon a limited number of chemical inhibitors to which resistance has already emerged. New control strategies are urgently needed. This research will investigate a novel mechanism for release of infection material recently discovered in Phytophthora cells, and will increase our understanding of how Phytophthora infects host plants, providing vital information required for the development of new, environmentally-safe inhibitors. Read moreRead less
Regulator Of G-protein Signalling-5: A Key Modulator Of Vascular Maturation And The
Funder
National Health and Medical Research Council
Funding Amount
$548,396.00
Summary
Tumours progressively grow in part because they escape destruction by the immune system. New blood vessels grow inside tumours by a process called angiogenesis, which in turn stops disease-fighting cells in their tracks. However, we have now discovered that it is possible to reverse angiogenesis by normalising the blood vessels. This effectively means the barriers are broken down and the tumour can be opened to the immune system or cancer fighting drugs. Furthermore, we have identified a protein ....Tumours progressively grow in part because they escape destruction by the immune system. New blood vessels grow inside tumours by a process called angiogenesis, which in turn stops disease-fighting cells in their tracks. However, we have now discovered that it is possible to reverse angiogenesis by normalising the blood vessels. This effectively means the barriers are broken down and the tumour can be opened to the immune system or cancer fighting drugs. Furthermore, we have identified a protein which appears to be very important for normalisation, a process which is currently not well understood. This proposal continues our pioneering work on vessel normalisation and will use models of highest clinical relevance to study the dynamics of vessel remodelling in tumours. Our approach is different to current angiogenesis research which simply tries to block or destroy the blood vessels that feed tumours. We expect our findings to lead to highly specific and effective anti-tumour therapies. Moreover, vessel growth in tumours has striking parallels to other vascular processes in the body, which have important implications for major and common human diseases such as high blood pressure and atherosclerosis. We now have the tools to study these processes and their abnormalities in our newly established disease model. By gaining insight into these disorders we will be able to develop novel approaches to stop disease progression.Read moreRead less
Molecular basis of the interaction between plant disease resistance proteins and pathogen avirulence proteins. Management of crop diseases involves the integrated use of resistant cultivars and the application of chemical pesticides. Many diseases, however, including rust, continue to pose an economically significant threat to agricultural productivity in Australia. The research outlined in this proposal aims to understand the mechanisms, at a molecular and structural level, that enable resistan ....Molecular basis of the interaction between plant disease resistance proteins and pathogen avirulence proteins. Management of crop diseases involves the integrated use of resistant cultivars and the application of chemical pesticides. Many diseases, however, including rust, continue to pose an economically significant threat to agricultural productivity in Australia. The research outlined in this proposal aims to understand the mechanisms, at a molecular and structural level, that enable resistant plants to detect and respond to pathogen attack. The outcomes of this currently unavailable fundamental understanding will enable new, durable and more effective resistance genes to be engineered. Therefore, the work has significant economic and environmental implications for agricultural crop plant productivity in this country.Read moreRead less
Active Transport Of Calcium Across Dental Enamel Cells - Testing A New Paradigm
Funder
National Health and Medical Research Council
Funding Amount
$258,000.00
Summary
Dental enamel defects and tooth loss affect over half our population, resulting in substantial suffering and economic costs. It is likely that many enamel defects could be prevented, and replacement teeth made more lifelike, if more was known about the cells responsible for producing enamel. A particular problem is our lack of understanding about how enamel-forming cells avoid overdosing on calcium, which can lead to cellular toxicity. The overall aim of this research is to use the latest cell b ....Dental enamel defects and tooth loss affect over half our population, resulting in substantial suffering and economic costs. It is likely that many enamel defects could be prevented, and replacement teeth made more lifelike, if more was known about the cells responsible for producing enamel. A particular problem is our lack of understanding about how enamel-forming cells avoid overdosing on calcium, which can lead to cellular toxicity. The overall aim of this research is to use the latest cell biology and biochemical techniques to elucidate the mechanisms of calcium handling in enamel cells, with developing teeth from rat as the experimental model. Our focus is on calcium transport mechanisms, a field where past theories were overturned by our recent findings with gene-knockout animals. We will test a new theory that has arisen from our investigations, using drugs and gene-silencing techniques to interfere with the cellular machinery now thought to be crucial for transporting calcium. By providing strong physiological evidence for this new mechanism, our expected results will define specific proteins that might be targeted by drugs and nutrition, and provide important information about how dietary fluoride and caffeine affect enamel quality. These findings would change thinking about how enamel defects can be prevented and provide a solid foundation to the exciting new field of dental bioengineering, whose goal is to coax stem cells to make natural replacement teeth.Read moreRead less
Structural studies of plant disease resistance proteins. Plant cells have evolved a gene-for-gene disease resistance mechanism, involving an interaction of a plant-derived receptor with a specific pathogen-derived molecule. Currently, plant breeders are restricted to the resistance genes available in particular crop species or sexually compatible relatives. In the last few years, several plant disease resistance genes have been identified, providing a foundation for studying the molecular basis ....Structural studies of plant disease resistance proteins. Plant cells have evolved a gene-for-gene disease resistance mechanism, involving an interaction of a plant-derived receptor with a specific pathogen-derived molecule. Currently, plant breeders are restricted to the resistance genes available in particular crop species or sexually compatible relatives. In the last few years, several plant disease resistance genes have been identified, providing a foundation for studying the molecular basis of the resistance process. We propose to obtain three-dimensional structural information on representative R proteins and their ligand complexes. This will form the basis for modifying existing resistance genes to confer resistance to new diseases, resulting in large economic benefits.Read moreRead less