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Directed Molecular Evolution Of G Protein-coupled Receptors For Stable And Functional Expression In Escherichia Coli
Funder
National Health and Medical Research Council
Funding Amount
$383,479.00
Summary
Approximately half of all prescription drugs on the market act on G protein coupled receptors (GPCRs). The mechanisms underlying GPCR function are mainly unknown due to a lack of structural information. No solved structures exist for any of the estimated 800 human GPCRs, making it difficult to design new drugs. By applying advanced protein engineering techniques I aim to produce human GPCRs in bacteria to ultimately acquire structural information, which will enable novel drug development.
Spatial And Temporal Dimensions Of Mu-opioid Receptor Signalling: Implications For The Development Of Tolerance
Funder
National Health and Medical Research Council
Funding Amount
$799,316.00
Summary
The use of morphine as an analgesic is still limited by undesirable side effects such as tolerance. Despite decades of research, the mechanisms behind the development of tolerance are poorly understood. The ? opioid receptor is a protein expressed at the surface of the cells that is the target of morphine. This project will investigate the signalling events triggered by opioids with unprecedented resolution and will aim to elucidate why morphine elicits more tolerance than other opioid drugs.
Structural Basis For Targeting Wnt Signalling Pathway In Cancer
Funder
National Health and Medical Research Council
Funding Amount
$645,205.00
Summary
Cells sense and respond to a variety of stimuli by activating different signaling pathways. The Wnt pathway is important in embryonic development as it controls cell division and specialization. In adults, dysregulation of this pathway can lead to aberrant cell division and cancer. This proposal will use structural biology to look at several steps of this pathway at the molecular level. This will provide answers on how this pathway works and will lead to new ways to target it therapeutically.
Developing Novel Peptide-based Therapeutics And Technologies To Mitigate Fibrosis
Funder
National Health and Medical Research Council
Funding Amount
$1,161,383.00
Summary
Fibrosis (tissue scarring) is an unmet medical problem that adversely affects both human health and medical devices. It causes organ (e.g. heart, kidney) failure leading to death. Fibrotic encapsulation causes medical device (e.g. surgical mesh) failure. Our team has discovered a peptide, B7-33, that mitigates fibrosis in the short-term. Our IDEAS grant aims to develop long-acting B7-33 therapies and, to employ long-acting B7-33 mimetics in anti-fibrotic compositions for surgical meshes.
Understanding Novel Drug Binding Pockets At G Protein-coupled Receptors
Funder
National Health and Medical Research Council
Funding Amount
$425,538.00
Summary
Cell-surface proteins exhibit multiple secondary binding sites for which only synthetic drugs have been identified so far. My hypothesis is that these secondary binding sites are common to most proteins because they are primarily targeted by largely yet unidentified endogenously released molecules that can modify the biology of these proteins.
This research will push the boundaries of current knowledge in receptor pharmacology and translate this knowledge into clinical outcomes. Receptors are proteins on the surface of our cells that bind hormones, neurotransmitters and pharmaceuticals. By better understanding the complexities of how these receptors work at the molecular level, the objective is to develop improved treatments and better clinical management for a range of medical conditions.
Debilitating anxiety disorders, such as post-traumatic stress disorder or panic disorder, affect 14% of adult Australians and current therapy is often ineffective. The amygdala is a brain region that is key to learning fear responses but also in reducing our fear responses. This project will determine whether the brain’s own endogenous opioids can modify the activity of the amygdala in order to provide new leads for novel pharmacotherapies with enhanced efficacy.
Mechanisms Of Ligand-Selective Signalling By Chemokine Receptors
Funder
National Health and Medical Research Council
Funding Amount
$749,428.00
Summary
Receptors are molecules located on the surfaces of cells. They control the response of one cell to chemical signals emitted by different cells. In this project we aim to characterise and understand the molecular details of how a receptor can respond differently to distinct chemical signals. The results of this study will help to guide future development of medicines to control white blood cell migration into tissues during inflammatory diseases such as heart disease, diabetes and arthritis.