DNA end resection: from basic mechanisms to genome editing. The project aims to understand processes underlying genome editing, a bioengineering process that introduces specific mutations into genomic DNA. Homologous recombination and nonhomologous end-joining pathways play a crucial role in repairing broken DNA strands, which are a toxic form of DNA damage. The proteins that function in the repair process have been recently identified, but it remains unclear how they function on a mechanistic l ....DNA end resection: from basic mechanisms to genome editing. The project aims to understand processes underlying genome editing, a bioengineering process that introduces specific mutations into genomic DNA. Homologous recombination and nonhomologous end-joining pathways play a crucial role in repairing broken DNA strands, which are a toxic form of DNA damage. The proteins that function in the repair process have been recently identified, but it remains unclear how they function on a mechanistic level and how either of the two main pathways is selected. The project aims to define how the activity of a key control protein, Sae2 (Sporulation in the Absence of Spo Eleven), is regulated by posttranslational modifications, and how this activates homologous recombination. The project plans to first use Saccharomyces cerevisiae yeast as a model and then to extend research into the human system in an attempt to improve the efficiency of genome editing. Read moreRead less
Special Research Initiatives - Grant ID: SR0354892
Funder
Australian Research Council
Funding Amount
$40,000.00
Summary
The Australian Protease Network. Proteases are pivotal enzymes during birth, life, ageing and death of all organisms. Proteases regulate most physiological processes by controlling protein activation, synthesis and turnover and are essential for replication and spread of viruses, bacteria and parasites that cause infectious diseases. Blockbuster drugs and diagnostics already target a few proteases. Australians have made innovative contributions individually to understanding and regulating these ....The Australian Protease Network. Proteases are pivotal enzymes during birth, life, ageing and death of all organisms. Proteases regulate most physiological processes by controlling protein activation, synthesis and turnover and are essential for replication and spread of viruses, bacteria and parasites that cause infectious diseases. Blockbuster drugs and diagnostics already target a few proteases. Australians have made innovative contributions individually to understanding and regulating these enzymes. However this initiative aims to network their efforts by value-adding to the current protease research through promoting national and international collaborations to improve our understanding of biology, and encourage exploitation of proteases/inhibitors/receptors for pharmaceutical and industrial applications.Read moreRead less
MOLECULAR APPROACHES TO OVERCOME SCABIES AND ASSOCIATED DISEASE. Scabies causes childhood pyoderma predisposing to severe disease in later life. It is a major increasing health burden in Indigenous people of Northern Australia. Drug resistance is developing in mites and bacteria. The lack of clinical material has hampered molecular research and this work will use comparative genomics of parasitic and free living mites and microbiome analysis to understand fundamental aspects of mite biology and ....MOLECULAR APPROACHES TO OVERCOME SCABIES AND ASSOCIATED DISEASE. Scabies causes childhood pyoderma predisposing to severe disease in later life. It is a major increasing health burden in Indigenous people of Northern Australia. Drug resistance is developing in mites and bacteria. The lack of clinical material has hampered molecular research and this work will use comparative genomics of parasitic and free living mites and microbiome analysis to understand fundamental aspects of mite biology and pathogenesis. The understanding of proteins that are essential for mite survival and interfere with host defences will allow the informed design of peptide inhibitors as a new strategy to develop alternative treatment options.Read moreRead less
Regulation of cell surface sialylation by targeting the CMP-sialic acid transporter and sialyltransferase: Towards the development of anti-metastatic agents. The mortality rates for many of the cancers afflicting the world's population are mirrored in Australia, particularly colon cancer. It's generally accepted that colon cancer, and cancers as a whole, are a significant healthcare issue in this country, representing a major challenge to biomedical researchers and healthcare professional. The e ....Regulation of cell surface sialylation by targeting the CMP-sialic acid transporter and sialyltransferase: Towards the development of anti-metastatic agents. The mortality rates for many of the cancers afflicting the world's population are mirrored in Australia, particularly colon cancer. It's generally accepted that colon cancer, and cancers as a whole, are a significant healthcare issue in this country, representing a major challenge to biomedical researchers and healthcare professional. The economic and social impact is immense, placing a huge strain on the healthcare system, as well as on the families affected. Any alternative treatment reducing cancer metastasis would be of enormous national and international benefit. It's believed that the significant studies outlined in this proposal, which are based on exciting preliminary data, will make a sizeable contribution to achieving this goal.Read moreRead less
Molecular mechanisms of pilin glycosylation in Neisseria: a model system for protein glycosylation in bacteria. The disease causing bacteria Neisseria meningitidis and Neisseria gonorrhoeae are important human pathogens. Cell surface structures, called pili, are known to be important in allowing the bacteria to stick to host cells. Genetic and structural studies have identified that the protein subunits, which make up pili, are glycosylated - modified by the addition of sugars. Until recently ....Molecular mechanisms of pilin glycosylation in Neisseria: a model system for protein glycosylation in bacteria. The disease causing bacteria Neisseria meningitidis and Neisseria gonorrhoeae are important human pathogens. Cell surface structures, called pili, are known to be important in allowing the bacteria to stick to host cells. Genetic and structural studies have identified that the protein subunits, which make up pili, are glycosylated - modified by the addition of sugars. Until recently glycosylation of Gram-negative bacterial proteins was not thought to occur, however our recent work with these bacteria, and other groups studying Pseudomonas and Campylobacter, have shown that this process may be widespread. In our previous studies, we have identified and analysed a number of genes involved in pili glycosylation, in bacteria, which make known sugar structures. We have used this information to developed models for how the biochemistry and physiology of the glycosylation system may work. With a well-established structure and many genes already identified, glycosylation in Neisseria represents the best available model system to study this novel and important process. In the proposed study we describe experiments planned to test our models and reveal the molecular detail of this process. This study could lead to major advances in our understanding of this process and, when understood, may have future applications in biotechnology.Read moreRead less
Genetic Basis of Variable Expression of Glycan Xeno-Autoantigens by Cattle. Meat and dairy products from cattle contain sugar structures (glycans) that are not made by humans. These structures can be recognised by the immune system and lead to allergic reactions, inflammation and potentially cancer. These non-human structures are called xeno-autoantigens or XAs. We have discovered individual cattle that do not produce one of these XAs. We will study the gene required to make XA in the XA-free ca ....Genetic Basis of Variable Expression of Glycan Xeno-Autoantigens by Cattle. Meat and dairy products from cattle contain sugar structures (glycans) that are not made by humans. These structures can be recognised by the immune system and lead to allergic reactions, inflammation and potentially cancer. These non-human structures are called xeno-autoantigens or XAs. We have discovered individual cattle that do not produce one of these XAs. We will study the gene required to make XA in the XA-free cattle to find the underlying mutation. The same approach will be used to look for natural XA-free individuals in other food species. This knowledge may enable us to create a test to facilitate the natural breeding of non-GMO, XA-free livestock to benefit Australian primary producers and provide safer food for consumers.Read moreRead less
Developing orthogonal synthetic signaling cascades. This project proposes a generic approach for the construction of molecular switches based on artificially autoinhibited proteases. The bottom-up design of protein-based signaling networks is a key goal of synthetic biology. Yet, this remains elusive due to our inability to tailor-make signal transducers and receptors that can be readily compiled into defined signaling networks. Using structure-guided design and directed protein evolution, a set ....Developing orthogonal synthetic signaling cascades. This project proposes a generic approach for the construction of molecular switches based on artificially autoinhibited proteases. The bottom-up design of protein-based signaling networks is a key goal of synthetic biology. Yet, this remains elusive due to our inability to tailor-make signal transducers and receptors that can be readily compiled into defined signaling networks. Using structure-guided design and directed protein evolution, a set of protease-based signal transducers and ligand activated allosteric receptors will be created. The developed components are intended to be used to construct artificial signaling networks in mammalian cells that are orthogonal to the endogenous signaling cascades.Read moreRead less
The protein O-glycosylation pathway in Neisseria meningitidis. Neisseria meningitidis causes bacterial meningitis, a sudden and severe disease of particular concern to children in both the developed and developing worlds. This project will contribute to an understanding of how these bacteria evade the immune system by modifying the proteins displayed on their surface, which will help in the development of a vaccine.
Development of therapeutic agents that target carbonic anhydrase enzymes. This research will discover new chemical entities (compounds) that may lead to therapies for the treatment of cancer, glaucoma and malaria. The research underpins a mechanism to add value to our compounds before partnering with industry to transform the discoveries made here to deliverable therapies that could benefit the health of millions, thus offering a potentially high value contribution to the Australian economy. The ....Development of therapeutic agents that target carbonic anhydrase enzymes. This research will discover new chemical entities (compounds) that may lead to therapies for the treatment of cancer, glaucoma and malaria. The research underpins a mechanism to add value to our compounds before partnering with industry to transform the discoveries made here to deliverable therapies that could benefit the health of millions, thus offering a potentially high value contribution to the Australian economy. The experience and commitment of the multi-disciplinary network of researchers offers exceptional training and employment opportunities for tomorrow's scientists in techniques for discovery and characterisation of novel chemicals, and their interaction with disease targets.Read moreRead less
Australian Laureate Fellowships - Grant ID: FL0992138
Funder
Australian Research Council
Funding Amount
$3,100,000.00
Summary
Towards antibacterials without resistance. Innovative automation technologies will be used to create and investigate a revolutionary new approach to disable pathogenic superbugs, bacteria resistant to multiple antibiotics. The chemicals created and proteins evaluated in this research program will advance fundamental knowledge about the molecular weapons that bacteria produce to cause disease; deliver social and economic benefits to Australia through the development of potential new antibacterial ....Towards antibacterials without resistance. Innovative automation technologies will be used to create and investigate a revolutionary new approach to disable pathogenic superbugs, bacteria resistant to multiple antibiotics. The chemicals created and proteins evaluated in this research program will advance fundamental knowledge about the molecular weapons that bacteria produce to cause disease; deliver social and economic benefits to Australia through the development of potential new antibacterial treatments; contribute to Australia's continued international leading role in drug discovery research; enhance international links and attract industry investment in Australia; and provide a stimulating research training environment to inspire and motivate the next generation of scientists.Read moreRead less