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.
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.
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.
Pharmacological Investigation Of The Glucagon-Like Peptide-1 Receptor (GLP-1R)
Funder
National Health and Medical Research Council
Funding Amount
$367,948.00
Summary
Family B G protein-coupled receptors represent key therapeutic targets for many conditions, including metabolic, bone, growth and neuronal disorders. However, poor mechanistic understanding of this receptor family impacts on their clinical value. Consequently, this research is aimed at gaining a more comprehensive understanding of the structure and function of the family B glucagon-like peptide-1 receptor through use of new and novel pharmacological techniques.
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 Major Class Of Cell Surface Drug Targets
Funder
National Health and Medical Research Council
Funding Amount
$7,595,840.00
Summary
G Protein-Coupled Receptors (GPCRs) form the largest family of receptors and drug targets in living organisms. Currently, the major reason that new drugs fail to reach the clinic is lack of appropriate drug effect (approx. 30%). Thus, we need a better understanding of how GPCRs work and how this relates to disease. Our Program addresses this knowledge gap, using GPCR models that are relevant to treatment of metabolic, inflammatory, cardiovascular and central nervous system disease.
Allosteric Modulation And Biased Signalling At The Calcium-sensing Receptor
Funder
National Health and Medical Research Council
Funding Amount
$636,242.00
Summary
The calcium-sensing receptor is a major target for the treatment of endocrine and bone disorders. However, the development of drugs for this receptor is challenging due to limited understanding of potential sites of drug interaction and how individual drugs may differentially change signalling from the receptor. This project will address these critical knowledge gaps, which may allow for improved therapeutic outcomes.
Role Of Extracellular Surface Residues In Agonist Activation Of The Alpha1 Adrenoceptor
Funder
National Health and Medical Research Council
Funding Amount
$414,786.00
Summary
Most modern drugs act on a class of cellular proteins known as GPCRs. Despite their importance, little is known about how agonists acting from the outside of cells produce a change in GPCR structure allowing signalling to the cell's interior. We have identified new residues on the extracellular surface of the alpha1 adrenoceptor that dramatically affect agonist responses, opening the door to understanding the molecular process of GPCR activation and the development of drugs that can target diffe ....Most modern drugs act on a class of cellular proteins known as GPCRs. Despite their importance, little is known about how agonists acting from the outside of cells produce a change in GPCR structure allowing signalling to the cell's interior. We have identified new residues on the extracellular surface of the alpha1 adrenoceptor that dramatically affect agonist responses, opening the door to understanding the molecular process of GPCR activation and the development of drugs that can target different GPCR conformations.Read moreRead less
Novel Approaches To The Targeting Of GPCRs Towards Improved Treatment Of Schizophrenia
Funder
National Health and Medical Research Council
Funding Amount
$415,218.00
Summary
The focus of these studies are two important types of brain proteins that have been implicated in various symptoms associated with schizophrenia. The aim is to exploit two emerging paradigms of drug action at these brain proteins that will allow us to target them in a more selective manner. In particular, these studies will provide a starting point for safer, more effective treatments for schizophrenia.
Enhancing The Blood-brain Barrier Efflux Of ?-amyloid: A Novel Approach For The Treatment Of Alzheimer’s Disease
Funder
National Health and Medical Research Council
Funding Amount
$291,274.00
Summary
Alzheimer’s disease (AD) is the leading cause of dementia and is associated with the accumulation of a toxic protein in the brain. This project will investigate whether enhancing the removal of this toxic protein from the brain (by shuttling it into the blood) will restore the memory deficit associated with AD. The outcomes of this project have the potential to lead to novel strategies for the treatment of this debilitating disorder.