Therapeutic Approaches To Circumvent NO• Resistance In The Type 2 Diabetic Heart And Vasculature
Funder
National Health and Medical Research Council
Funding Amount
$563,337.00
Summary
Type 2 diabetes (T2D) is Australia’s fastest growing chronic disease, affecting almost 2 million Australians (who face poor cardiovascular health outcomes). We have discovered an exciting new avenue that may potentially more effectively counteract heart and blood vessel disorders in T2D patients in an acute cardiovascular emergency, of substantial clinical importance.
Pharmacological Inhibition Of IRAP As A Novel Antifibrotic Strategy
Funder
National Health and Medical Research Council
Funding Amount
$1,036,370.00
Summary
There are very few treatments that can reduce heart stiffening, called fibrosis, which is seen in patients with high blood pressure or in patients who have had a heart attack. This project will test new drugs that we have developed that act by a unique mechanism to reverse or prevent cardiovascular disease in patients with poorly-functioning hearts and blood vessels.
Formyl Peptide Receptor Biased Agonists As Novel Cardioprotective Agents Against Myocardial Infarction.
Funder
National Health and Medical Research Council
Funding Amount
$318,768.00
Summary
Heart attack and its resulting heart failure are the leading causes of death in Australia. Examining a promising new target (formyl peptide receptors), I will use my knowledge of drug action at the single cell level to identify new drugs that act via a unique biased mechanism. These will be tested in pre-clinical animal models of heart attack to uncover critical new potential therapies that will protect the heart post heart attack and prevent the development heart failure.
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.
Adenosine Receptor Context-Specific Biased Agonism To Treat Ischaemic Heart Disease
Funder
National Health and Medical Research Council
Funding Amount
$1,021,744.00
Summary
Heart attacks and secondary heart failure remain significant health burdens. Stimulation of adenosine receptors located on heart cells confers powerful cardiac protection, improving acute and longer-term heart function subsequent to a heart attack but avoiding the usual unwanted effects from this approach. We aim to better understand the mechanism of action of potential adenosine receptor therapeutics and establish the clinical potential of these compounds using animal models of heart failure.
Biased Allosteric Modulators Of Metabotropic Glutamate Receptors: Novel Therapeutic Targets For CNS Disorders
Funder
National Health and Medical Research Council
Funding Amount
$611,534.00
Summary
Metabotropic glutamate receptor 5 (mGlu5) is a major therapeutic target for depression and schizophrenia. The proposed studies will improve our understanding of how drug-like chemicals interact with mGlu5 and therefore change the activity of these receptors and in turn the activity of brain cells leading to therapeutic effectiveness. The research undertaken in this program will allow us to be smarter in developing new mGlu5 drugs that are both effective and have minimal side effects.
Understanding Allosteric Modulation And Biased Signalling At Family B GPCRs
Funder
National Health and Medical Research Council
Funding Amount
$428,065.00
Summary
Family B GPCRs are therapeutic targets for drugs treating osteoporosis, hypercalcaemia, Paget’s disease, type II diabetes and are being actively pursued for other diseases that represent major global health burdens. Despite huge financial input, there are no orally available drugs that act on these receptors. This speaks to a lack of mechanistic understanding of how they work. My research focuses on addressing this question and how to exploit these receptors to design and identify better drugs.
Towards The Rational Design Of Calcium Sensing Receptor Allosteric Modulators For The Treatment Of Osteoporosis And Calcium Handling Disorders
Funder
National Health and Medical Research Council
Funding Amount
$741,390.00
Summary
Drugs that target the human calcium sensing receptor can be too strong or too weak, resulting in side effects or lack of efficacy. This proposal thus seeks to establish whether the strength of drug activity can be rationally altered and exploited to treat different disease states by fine-tuning CaSR activity in a disease-specific manner.
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.