This project will investigate the properties of an important family of proteins that play a major role in diseases such as chronic pain and cardiovascular illnesses. It will apply multidisciplinary, cutting-edge, approaches to understand how different types of drugs act on these proteins, and use this information to develop novel drug leads that can modulate these proteins in a more selective and efficacious manner, with a particular emphasis on targeting chronic pain conditions.
The Importance Of Receptor Trafficking For Signalling Of Pain And Inflammation
Funder
National Health and Medical Research Council
Funding Amount
$787,604.00
Summary
Inflammation and pain are normal processes that are essential for survival: inflammation fights infections and pain allows avoidance of danger. These processes are normally tightly controlled and are transient. During disease, they become dysregulated and chronic. By understanding the normal processes of inflammation and pain, and by determining how dysregulation causes disease, we aim to develop new treatments for diseases that are a major cause of human suffering.
Engendering Biased Signalling At The Human Calcium Sensing Receptor (CaSR) To Correct Pathophysiology
Funder
National Health and Medical Research Council
Funding Amount
$633,860.00
Summary
The human calcium sensing receptor (CaSR) has been targeted therapeutically in hyperparathyroidism and osteoporosis, but current CaSR therapeutics exhibit problematic side effects or are ineffective. Thus, the current research proposal seeks to understand the specific properties of CaSR drugs required to selectively control whole body calcium and bone mineral metabolism, to identify ligands that can mediate desired therapeutic effects at the exclusion of adverse effects.
Integrated Approaches To Targeting G Protein-coupled Receptors: Translational Studies Of Novel Drug-receptor Paradigms
Funder
National Health and Medical Research Council
Funding Amount
$851,980.00
Summary
This Fellowship focuses on one of the largest family of proteins found in the human body, the so-called ‘G protein-coupled receptors ‘ (GPCRs). GPCRs control how each of our cells communicates with one another, and have been implicated in virtually all diseases. This proposal will study new mechanisms of targeting drugs to GPCRs that can overcome current drug discovery bottlenecks and lead to new ways of treating neuropsychiatric, cardiovascular, inflammatory and metabolic diseases.
The Structural Basis For Biased Agonism At The Glucagon-like Peptide-1 Receptor
Funder
National Health and Medical Research Council
Funding Amount
$872,536.00
Summary
The glucagon-like peptide-1 receptor plays an essential role in nutrient-regulated insulin release, and is a major target for therapeutic treatment of type 2 diabetes. The binding of different drugs to this receptor can promote distinct signalling profiles inside the cell that can lead to different physiological outcomes. Understanding the mechanistic basis for this will provide a framework to enable rational design of novel, better and safer therapeutics for the treatment of diabetes.
Research Fellowship: Understanding G Protein-coupled Receptors (GPCRs)
Funder
National Health and Medical Research Council
Funding Amount
$444,177.00
Summary
This project focuses on drug action at G protein-coupled receptors (GPCRs), the largest class of drug targets. It builds on key discoveries by the applicant that novel sites on GPCRs can be targeted by small molecules in a selective manner, thus minimizing side effects and maximizing therapeutic efficacy. Because this approach can work across most GPCR families, the relevance to the pharmaceutical industry and GPCR-related diseases, such as schizophrenia and diabetes, is very high.
Cytoprotective And Metabolic Responses To Biased Agonists Acting At Cardiomyocyte Gq-coupled Receptors
Funder
National Health and Medical Research Council
Funding Amount
$723,742.00
Summary
Cell surface receptors mediate the response of cardiac muscle cells to hormones and transmitters by interacting with a repertoire of intracellular signalling proteins. Despite primary coupling to Gq proteins that activate shared pathways, four such receptors promote differing responses in cardiac cells. We will investigate signalling pathways differentially activated by the ?1A-adrenergic receptor that promote survival of cardiac muscle under conditions of cell damage or nutrient insufficiency.
Understanding The Structural Basis For Family B G Protein-coupled Receptor Function
Funder
National Health and Medical Research Council
Funding Amount
$745,082.00
Summary
G protein-coupled receptors (GPCRs) are the largest family of cell surface proteins that enable communication from external signals to the inside of cells of the body. Family B GPCRs are a therapeutically important subclass of these receptors and they play crucial roles in bone and energy homeostasis, cardiovascular control and immune response. This grant will uncover fundamental knowledge on how these receptors work, and will enhance future development of therapeutics.
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.
Is Overactive Bladder A 'Bladder Itch'? Identification Of Itch Specific Pathways Within The Bladder
Funder
National Health and Medical Research Council
Funding Amount
$720,585.00
Summary
Overactive bladder is a leading cause of nocturia, urgency and incontinence. These symptoms arise from sensory nerve fibres in the bladder. We have identified key irritant mechanisms, including the bile acid receptor TGR5 and Mrgpr family, thought to only exist in the skin, also innervate the bladder. We hypothesis that the clinical entity overactive bladder, is triggered by pathological activation of bladder afferents by such irritants and that overactive bladder is essentially a bladder itch.