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Enhanced biocatalysis in organic solvents for pharmaceutical biotransformation. Enzymes such as hydrolases play an important role in biotechnology because of their extreme versatility with respect to substrate specificity and stereoselectivity. The use of lipases as catalysts for optical isomer-specific organic reactions is often limited by unacceptably low enantioselectivities. We will investigate recombinant enzymes cloned from thermophilic lipolytic bacteria for synthetic reactions in orga ....Enhanced biocatalysis in organic solvents for pharmaceutical biotransformation. Enzymes such as hydrolases play an important role in biotechnology because of their extreme versatility with respect to substrate specificity and stereoselectivity. The use of lipases as catalysts for optical isomer-specific organic reactions is often limited by unacceptably low enantioselectivities. We will investigate recombinant enzymes cloned from thermophilic lipolytic bacteria for synthetic reactions in organic solvents, especially chiral resolution of mixtures in the production of pharmaceutical intermediates. Genetic improvement of lipase enantiospecificity and regioselectivity will be achieved using in vitro evolution by recombination and screening. The outcome will be cost-effective production superior biocatalysts with specifically enhanced regiospecific, enantioselective and hydrolytic characteristics.
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How organisms coordinate energy supply and demand. The metabolic stress sensing protein kinase called the AMP activated protein kinase controls metabolism of all eukaryotes to meet the needs of energy demand and nutrient supply. It is responsible for accelerating metabolism (glucose transport, glycolysis and fatty acid oxidation) in response to energy demand and with caloric restriction it regulates gene transcription to adapt to energy supply. This project is to provide a comprehensive unders ....How organisms coordinate energy supply and demand. The metabolic stress sensing protein kinase called the AMP activated protein kinase controls metabolism of all eukaryotes to meet the needs of energy demand and nutrient supply. It is responsible for accelerating metabolism (glucose transport, glycolysis and fatty acid oxidation) in response to energy demand and with caloric restriction it regulates gene transcription to adapt to energy supply. This project is to provide a comprehensive understanding of the AMP activated protein kinase (enzyme isoforms, genes, physiological roles and regulation). This knowledge will have major benefits in biopharmaceutical development, the livestock, plant and sport/racing industries.Read moreRead less
Functional Genomics to Predict and Enhance Response to Interferon. The increasing number and huge cost impost of new therapies to health providers, both worldwide and nationally, has not yet resulted in a concomitant increase in strategies to optimise their use. Many of the new therapies are proteins (recombinant human proteins or humanised monoclonal antibodies). The improved use of one of Australia's most expensive commonly used protein drugs, pegylated interferon ribavirin (Peg-IFN-R), could ....Functional Genomics to Predict and Enhance Response to Interferon. The increasing number and huge cost impost of new therapies to health providers, both worldwide and nationally, has not yet resulted in a concomitant increase in strategies to optimise their use. Many of the new therapies are proteins (recombinant human proteins or humanised monoclonal antibodies). The improved use of one of Australia's most expensive commonly used protein drugs, pegylated interferon ribavirin (Peg-IFN-R), could potentially produce savings to the Pharmaceutical Benefits Scheme (PBS), and improve delivery of healthcare to thousands of Australians.Read moreRead less
Validating protozoa-specific drug targets using peptides from biodiverse gene fragment libraries. Cryptosporidium and the trypanosomes are protozoan parasites, which have a global impact on the health, survival and economic development of millions of people and animals world wide. New therapies for the diseases they cause are urgently required. We describe a novel means of identifying protozoa-specific peptides that will inhibit the formation of essential protein complexes, which have no effect ....Validating protozoa-specific drug targets using peptides from biodiverse gene fragment libraries. Cryptosporidium and the trypanosomes are protozoan parasites, which have a global impact on the health, survival and economic development of millions of people and animals world wide. New therapies for the diseases they cause are urgently required. We describe a novel means of identifying protozoa-specific peptides that will inhibit the formation of essential protein complexes, which have no effect on the mammalian host. Candidate peptides will then be used to validate these protein complexes as new targets for the development of peptide-based therapeutic compounds. This project will validate novel targets for the development of new treatments for these diseases.Read moreRead less
The Role of RNA interference in the induction of immune responses. Our work will allow us to understand a new means by which to alert the immune system to the presence of cancer cells using a new technology called RNA interference. This will hopefully lead to new investment in biotechnology products based on RNA interference, improved treatments for cancers and better health for Australians
Biosynthesis of nonribosomal peptide toxins in cyanobacteria: A functional characterisation of microcystin synthetase. Microcystins are potent toxins and tumour promoters produced by cyanobacteria associated with blue-green algal blooms. This non-ribosomal peptide is produced by microcystin synthetase, a unique enzyme complex comprised of peptide synthetases, polyketide synthases, and integrated accessory enzymes. We have identified and characterised the extensive gene cluster encoding this enzy ....Biosynthesis of nonribosomal peptide toxins in cyanobacteria: A functional characterisation of microcystin synthetase. Microcystins are potent toxins and tumour promoters produced by cyanobacteria associated with blue-green algal blooms. This non-ribosomal peptide is produced by microcystin synthetase, a unique enzyme complex comprised of peptide synthetases, polyketide synthases, and integrated accessory enzymes. We have identified and characterised the extensive gene cluster encoding this enzyme. This project describes the biochemical characterisation of specific enzyme activities within microcystin synthetase and how they determine the final structure and toxicity of the many forms of microcystin. Interactions between this enzyme complex and its substrate amino acids will provide information for the genetic engineering of this and similar natural products.Read moreRead less
BIOCATALYSTS MINED FROM CYTOCHROME P450 LIBRARIES: AN INNOVATIVE TOOL FOR ACCELERATING DRUG DEVELOPMENT. The cytochrome P450s (P450s) are a family of enzymes that are perhaps the most versatile biological catalysts known. DNA shuffling is an emerging technique that takes the genes encoding families of enzymes and creates libraries of catalysts with both improved and novel properties. We will obtain proof of concept that shuffled P450 libraries can be screened and optimized for use as biocatalys ....BIOCATALYSTS MINED FROM CYTOCHROME P450 LIBRARIES: AN INNOVATIVE TOOL FOR ACCELERATING DRUG DEVELOPMENT. The cytochrome P450s (P450s) are a family of enzymes that are perhaps the most versatile biological catalysts known. DNA shuffling is an emerging technique that takes the genes encoding families of enzymes and creates libraries of catalysts with both improved and novel properties. We will obtain proof of concept that shuffled P450 libraries can be screened and optimized for use as biocatalysts in drug development. The methodologies developed here will overcome two critical bottlenecks in current drug development: the optimisation and metabolic profiling of new drug candidates. This will yield important benefits in accelerating the optimisation and safety testing of drugs under development.Read moreRead less
Genetic and molecular analysis of long-distance gene silencing in Arabidopsis. Gene silencing is a surveillance mechanism in plants and animals to ensure that all genes are switched on or off at the right time. It is also a defence mechanism against viruses. Perturbation of gene silencing can be a cause of genetic diseases, and conversely, gene silencing has immense potential as a therapeutic tool for correcting genetic diseases and curing viral diseases. When silencing is triggered against a ge ....Genetic and molecular analysis of long-distance gene silencing in Arabidopsis. Gene silencing is a surveillance mechanism in plants and animals to ensure that all genes are switched on or off at the right time. It is also a defence mechanism against viruses. Perturbation of gene silencing can be a cause of genetic diseases, and conversely, gene silencing has immense potential as a therapeutic tool for correcting genetic diseases and curing viral diseases. When silencing is triggered against a gene or virus in plants, genetic signals are transmitted throughout the organism to systemically switch off the specific gene or virus. Expected long-term national/community benefits from understanding gene silencing are wide-ranging, from improved crops through to drugs and gene therapy.Read moreRead less
Engineering of anti-platelet antibodies for the diagnosis and therapy of infants with bleeding disorders. Foeto-maternal alloimmune thrombocytopenia (FMAIT) is a serious clinical condition where infants suffer potentially fatal bleeding disorders from 14 weeks gestation to 1-2 weeks post delivery. The cause of the disease is through maternal antibodies destroying foetal platelets. Our aim is to produce human antibodies, which will be used as diagnostic agents to screen for the condition in preg ....Engineering of anti-platelet antibodies for the diagnosis and therapy of infants with bleeding disorders. Foeto-maternal alloimmune thrombocytopenia (FMAIT) is a serious clinical condition where infants suffer potentially fatal bleeding disorders from 14 weeks gestation to 1-2 weeks post delivery. The cause of the disease is through maternal antibodies destroying foetal platelets. Our aim is to produce human antibodies, which will be used as diagnostic agents to screen for the condition in pregnant women, and to further develop such antibodies for therapy. Identification of mothers at risk of FMAIT and the development of a specific therapy are vital to the management and prevention of this serious condition.Read moreRead less
Identification of the targets of a novel metalloproteinase inhibitor used for the treatment of human head lice. Human head lice are difficult to control. This project examines a new type of ovicidal treatment that prevents louse eggs from hatching. The goal is to understand precisely how this treatment is ovicidal, so that even more effective products might be designed. Beyond the benefits of providing a safe and reliable treatment option for a troublesome pest, the development of this product ....Identification of the targets of a novel metalloproteinase inhibitor used for the treatment of human head lice. Human head lice are difficult to control. This project examines a new type of ovicidal treatment that prevents louse eggs from hatching. The goal is to understand precisely how this treatment is ovicidal, so that even more effective products might be designed. Beyond the benefits of providing a safe and reliable treatment option for a troublesome pest, the development of this product will be a significant step forward for the Australian pharmaceutical industry.Read moreRead less