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.
Are Novel Nitric Oxide Mimetics Protective In Vascular Disease?
Funder
National Health and Medical Research Council
Funding Amount
$634,044.00
Summary
Nitric oxide (NO) is a biologically active gas which controls blood flow and blood pressure. New drugs which mimic the effects of NO show promise in the treatment of cardiovascular disease. This study investigates the ability of NO mimetics to protect blood vessels in disease, by limiting the production of toxic molecules, improving blood flow and preventing blood clot formation. The information gained may lead to the development of new therapies for blood vessel diseases such as stroke.
Stroke is a devastating disease causing mortality and morbidity on a massive scale, and which still has no treatment besides a clot-buster that cannot be used in 90% of patients. This research should provide a better understanding of stroke pathology and identify new therapeutic directions. It will elucidate an unappreciated but crucial role of specific immune cells in brain injury after stroke, and hopefully lead to new ways to limit brain injury and promote recovery from stroke.
M2 Macrophage Polarization As A Cause Of Vascular Fibrosis And Stiffening In Hypertension
Funder
National Health and Medical Research Council
Funding Amount
$657,028.00
Summary
Blood vessel stiffening is a hallmark of hypertension (A.K.A. high blood pressure) and is thought to be a major contributor to the clinical complications of the condition, which include heart failure, stroke and renal impairment. Here we will test the novel concept that this stiffening process is caused by certain types of white blood cells (macrophages), which enter the walls of blood vessels and signal the surrounding cells to produce a rigid scaffolding protein called collagen.
Improving Endothelial Dysfunction In Diabetes-associated Vascular Diseases With Nrf2 Activators
Funder
National Health and Medical Research Council
Funding Amount
$340,039.00
Summary
Diabetic patients have a greater risk of developing cardiovascular diseases as compared to the general population. This is largely attributed to the impact the diabetic environment has on the endothelium (inner layer of the blood vessel). Indeed, clinical studies have shown that impaired endothelial function occurs prior to the development of cardiovascular diseases. Hence, we propose to study a novel way to improve endothelial function by limiting oxidative stress and inflammatory pathways.
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.
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.