Control of immune recognition and response by microbial metabolites. This project aims to study immune recognition of microbial metabolites and develop reagents to control immune responses. Chemical synthesis will be used to develop new antigens for unconventional T cells and the first soluble agonists and antagonists of a glycolipid-sensing immune receptor. Expected outcomes include the discovery of new immune effectors, broadening our knowledge of the repertoire of small molecules that can be ....Control of immune recognition and response by microbial metabolites. This project aims to study immune recognition of microbial metabolites and develop reagents to control immune responses. Chemical synthesis will be used to develop new antigens for unconventional T cells and the first soluble agonists and antagonists of a glycolipid-sensing immune receptor. Expected outcomes include the discovery of new immune effectors, broadening our knowledge of the repertoire of small molecules that can be sensed by the immune system, and developing chemical approaches to promote or dampen immune responses. Major benefits include research training in chemical biology, strengthened international linkages and fundamental insights into the chemical basis of immune recognition and response.Read moreRead less
Discovery Early Career Researcher Award - Grant ID: DE140100162
Funder
Australian Research Council
Funding Amount
$374,005.00
Summary
Enzymatic synthesis of pro-resolution lipid mediators: Towards new therapeutic strategies for inflammatory diseases. Inflammation is a major contributing factor in many diseases, including arthritis, Alzheimer's disease, multiple sclerosis, cardiovascular disease and cancer. It has recently been shown that the resolution of inflammation is an active biological process initiated by lipid mediators. The aim of this project is to synthesise and characterise pro-resolution lipid mediators, elucidate ....Enzymatic synthesis of pro-resolution lipid mediators: Towards new therapeutic strategies for inflammatory diseases. Inflammation is a major contributing factor in many diseases, including arthritis, Alzheimer's disease, multiple sclerosis, cardiovascular disease and cancer. It has recently been shown that the resolution of inflammation is an active biological process initiated by lipid mediators. The aim of this project is to synthesise and characterise pro-resolution lipid mediators, elucidate the enzyme cascades involved in their biosynthesis and explore their roles in the active resolution of inflammation. This project will provide a fundamental understanding of pro-resolution and anti-inflammatory pathways as well as new therapeutic target molecules for the treatment of inflammatory diseases.Read moreRead less
Unravelling the immunology of complex glycolipids by chemical synthesis. This project seeks to develop new approaches to chemically synthesise bacterial and fungal glycolipids and develop a molecular-level understanding of their effect on the immune system. Bacterial and fungal glycolipids are exotic chemical species that act as danger signals to prime and modulate our innate immune responses. These complex glycolipids possess powerful immunological activities that continue to shape our understa ....Unravelling the immunology of complex glycolipids by chemical synthesis. This project seeks to develop new approaches to chemically synthesise bacterial and fungal glycolipids and develop a molecular-level understanding of their effect on the immune system. Bacterial and fungal glycolipids are exotic chemical species that act as danger signals to prime and modulate our innate immune responses. These complex glycolipids possess powerful immunological activities that continue to shape our understanding of innate immunity, yet cannot be acquired from natural sources in the quantities and purity needed. The approaches expected to be developed in the project will be used to illuminate molecular details of immune signalling through pattern recognition receptors and presentation on specialised glycolipid antigen-presenting molecules. Outcomes may include new ways to fight disease and promote health by marshalling the resources of the immune system.Read moreRead less
Lymphotropic prodrugs: a novel mechanism for targeted drug delivery. This project aims to design chemically modified drugs that target drug delivery specifically to white blood cells. This approach promises to maximise drug action and simultaneously reduce toxicity for diseases where lymphocytes are the major drug target. These include autoimmune disease, leukaemia, lymphoma, HIV, transplant rejection and diabetes.
New platform technologies for the chemical synthesis of post-translationally modified proteins. The last decade has seen an explosion in the number of protein drugs approved for use in the clinic, a large proportion of which possess post-translational modifications (PTMs). These modified protein drugs are produced and sold as mixtures which has led to difficulties in understanding the role of specific PTMs on activity and in gaining clinical approval for candidate drugs. This project will provid ....New platform technologies for the chemical synthesis of post-translationally modified proteins. The last decade has seen an explosion in the number of protein drugs approved for use in the clinic, a large proportion of which possess post-translational modifications (PTMs). These modified protein drugs are produced and sold as mixtures which has led to difficulties in understanding the role of specific PTMs on activity and in gaining clinical approval for candidate drugs. This project will provide a fundamental solution to this problem through the development of novel synthetic methods and a powerful new platform technology for accessing PTM proteins in pure form. The utility of this technology will be demonstrated through its use in the total chemical synthesis of a range of PTM proteins for applications in biology and medicine.Read moreRead less
Deciphering novel cross-talk between innate cytokine receptors. Understanding the basic functions of interferons, how they signal to cells, is central to understanding fundamental immunity. Interferons are crucial molecules of the immune system that are important for normal cell development and they protect the body from viral infection and cancer but can be deleterious in different autoimmune diseases and trauma settings. Preliminary Data shows there is a pathway of interferon signalling that h ....Deciphering novel cross-talk between innate cytokine receptors. Understanding the basic functions of interferons, how they signal to cells, is central to understanding fundamental immunity. Interferons are crucial molecules of the immune system that are important for normal cell development and they protect the body from viral infection and cancer but can be deleterious in different autoimmune diseases and trauma settings. Preliminary Data shows there is a pathway of interferon signalling that has previously been overlooked. This project aims to understand how this pathway works and how it contributes to the normal workings of cells. This fundamental science has future consequences for the design of vaccines and for the design of therapeutics to treat diseases that show defective interferon signalling.Read moreRead less
Molecular Mechanisms of NOD signalling. Alterations in NOD1 and NOD2 (nucleotide-binding oligomerization domain containing 1 and 2) signalling have been implicated in various human inflammatory diseases. Therefore, a clear understanding of the molecular signalling pathways is important to gain further insights into potential drug targets for the treatment of these diseases. Using novel experimental approaches, this project aims to identify new members of the NOD signalling pathway. It will test ....Molecular Mechanisms of NOD signalling. Alterations in NOD1 and NOD2 (nucleotide-binding oligomerization domain containing 1 and 2) signalling have been implicated in various human inflammatory diseases. Therefore, a clear understanding of the molecular signalling pathways is important to gain further insights into potential drug targets for the treatment of these diseases. Using novel experimental approaches, this project aims to identify new members of the NOD signalling pathway. It will test the effect of pharmacological inhibition of established molecules such as RIPK2 or IAPs in NOD dependent models for human diseases. Outcomes of this study will be of the utmost interest for the treatment of NOD driven diseases such as Crohn's disease, Blau syndrome or asthma.Read moreRead less
Understanding endogenous allosteric modulators of G protein-coupled receptors. Major life science challenges include how chemicals outside cells signal to proteins inside, how this results in physiological responses, and how dysfunction of these processes leads to pathophysiology. Despite the critical importance of G protein-coupled receptors (GPCRs), much remains to be learned about their regulation by endogenous and synthetic molecules. This project aims to address this gap, by building on rec ....Understanding endogenous allosteric modulators of G protein-coupled receptors. Major life science challenges include how chemicals outside cells signal to proteins inside, how this results in physiological responses, and how dysfunction of these processes leads to pathophysiology. Despite the critical importance of G protein-coupled receptors (GPCRs), much remains to be learned about their regulation by endogenous and synthetic molecules. This project aims to address this gap, by building on recent ground-breaking studies that have been performed, by focusing on alternative binding sites of GPCRs called allosteric sites. The major hypothesis is that these allosteric sites are widespread across GPCRs because the body produces endogenous allosteric ligands that remain largely unidentified, but which can play vital roles in biology.Read moreRead less
Discovery Early Career Researcher Award - Grant ID: DE130100117
Funder
Australian Research Council
Funding Amount
$375,000.00
Summary
Allosteric fingerprinting of G protein-coupled receptor monomers and oligomers. Allosteric modulation describes interactions between distinct, but conformationally linked, binding sites. Research will develop enabling technology using the unique profile, or 'fingerprint', of allosteric modulation at interacting and non-interacting G protein-coupled receptors to probe for receptor complexes within healthy and diseased tissue.
Structural and functional analysis of the protein kinase R. We have shown that protein kinase R (PKR) plays a key role in regulating the body's response to virus infections, inflammation and cancer. This project will identify mechanisms that regulate the activity of PKR and provide information useful for the development of novel drugs.