Understanding the mechanisms of class B GPCR-transducer coupling. Current effort in developing drugs targeting G protein-coupled receptors (GPCRs) often result in low success rate due to the lack of understanding of the complexity and the spatiotemporal control of receptor function. The research program aims to understand the molecular mechanisms of receptor/transducer selectivity. The proposal integrated multi-disciplinary approaches to provide a deeper understanding of how the receptor is acti ....Understanding the mechanisms of class B GPCR-transducer coupling. Current effort in developing drugs targeting G protein-coupled receptors (GPCRs) often result in low success rate due to the lack of understanding of the complexity and the spatiotemporal control of receptor function. The research program aims to understand the molecular mechanisms of receptor/transducer selectivity. The proposal integrated multi-disciplinary approaches to provide a deeper understanding of how the receptor is activated responding to different ligands. The anticipated outcome including an enhanced capacity for understanding the fundamental biology, a stronger national and international collaborations. This will provide significant benefits including expanded basic knowledge and improvements in drug development efficiency. Read moreRead less
The molecular basis for efficacy at G protein coupled receptors. This project aims to investigate the molecular steps underlying the relationship between sensing by signal-transmitting proteins on the cell surface called G protein-coupled receptors and cellular response. The project aims to build on studies that have sought to understand the primary, molecular basis for this cellular volume control. This project seeks to use these novel approaches to fill this knowledge gap, providing a deeper u ....The molecular basis for efficacy at G protein coupled receptors. This project aims to investigate the molecular steps underlying the relationship between sensing by signal-transmitting proteins on the cell surface called G protein-coupled receptors and cellular response. The project aims to build on studies that have sought to understand the primary, molecular basis for this cellular volume control. This project seeks to use these novel approaches to fill this knowledge gap, providing a deeper understanding of how physiology and medicines work. The project expects to expand fundamental understanding of signal transmission at this receptor class. This project will deliver benefits including expanded basic knowledge and a contribution to future improvements in drug development.Read moreRead less
Discovering novel allosteric probes of muscarinic acetylcholine receptors. This project aims at fostering novel approaches to selectively target vital receptors in the human body, the muscarinic acetylcholine receptors (mAChRs). By harnessing the design of receptor mutations, compounds synthesis and fluorescent imaging, the project expects to develop new pharmacological tools for a family of receptors essential for the life of all vertebrates. By enriching our understanding of this family of rec ....Discovering novel allosteric probes of muscarinic acetylcholine receptors. This project aims at fostering novel approaches to selectively target vital receptors in the human body, the muscarinic acetylcholine receptors (mAChRs). By harnessing the design of receptor mutations, compounds synthesis and fluorescent imaging, the project expects to develop new pharmacological tools for a family of receptors essential for the life of all vertebrates. By enriching our understanding of this family of receptor, the project expects to provide significant benefits to the research field by impacting on future drug discovery efforts, not only at mAChRs, but at other structurally related receptors.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
Fibrosis is a key cause of renal pathology-dysfunction. Relaxin is an endogenous reno-protective factor, and thus has enormous therapeutic potential. However, despite compelling pre-clinical evidence of its efficacy, little is known about relaxin's mechanism of action. These studies will lead to a much better understanding of its signal transduction properties that will allow us to maximise its anti-fibrotic potential; identify new targets for intervention; and design better clinical trials.
Control of cell fate decisions in neurogenesis: use of embryonic stem cells to investigate key signalling systems and gene expression programs. Human embryonic stem cells (hESC) have the potential to provide an unlimited source of specific subtypes of human neurons for basic studies in neuroscience and biomedical applications. The use of hESC is limited at present by a lack of control over lineage commitment during differentiation in vitro. This project will use engineered reporter hESC lines t ....Control of cell fate decisions in neurogenesis: use of embryonic stem cells to investigate key signalling systems and gene expression programs. Human embryonic stem cells (hESC) have the potential to provide an unlimited source of specific subtypes of human neurons for basic studies in neuroscience and biomedical applications. The use of hESC is limited at present by a lack of control over lineage commitment during differentiation in vitro. This project will use engineered reporter hESC lines to investigate which cell signalling pathways and gene expression programs are involved in controlling cell fate. The project will result in improved protocols for hESC differentiation allowing enrichment of cultures with specific neuronal subtypes, and significant advances in the understanding of neuronal lineage commitment and maturation during brain development. 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.
The combined use of proteomics and small molecules for target identification and pathway analysis. This project intends to investigate how a series of new small molecules identified from our research to improve the metabolic effects of insulin. This project will integrate medicinal chemistry with proteomics and metabolic biology to identify the cellular targets and their mechanism of action.
Development and use of novel technologies to improve drugs targeting G protein-coupled receptor complexes involved in disease. The purpose of this project is to develop and use new and innovative technologies to improve many of the drugs taken for a wide range of medical conditions. The expected outcomes are the discovery of better drugs and a greater understanding of the drugs currently on the market, particularly enabling improved management of side-effects.