The Bcl-2 family of proteins is crucial for apoptosis (a form of programmed cell death) regulation. They target the mitochondrial outer membrane where they interact to determine cell fate. We will evaluate the membrane interactions of the Bcl-2 proteins in complementary biophysical and cellular experiments to redefine our understanding of the mechanism of apoptosis and provide new avenues for the development of compounds to selectively modulate diseases in which apoptosis is unregulated.
Development Of Selective Melanocortin Receptor Agonists And Antagonists
Funder
National Health and Medical Research Council
Funding Amount
$684,607.00
Summary
Human melanocortin receptors play a key role in a variety of physiological processes ranging from energy regulation, skin pigmentation and regulation of food intake. This project aims to generate novel peptide based molecules that will selectively interact with different melanocortin receptors to better understand their pharmacology thereby opening the potential for future drug development for obesity, stroke or inflammatory skin disorders.
Potent Small Molecule Modulators Of A Complement Protein In Inflammation
Funder
National Health and Medical Research Council
Funding Amount
$689,428.00
Summary
We have invented powerful new compounds that act on the cell surface and regulate inflammation. We plan to (1) fine-tune our small molecules for optimal activity on different kinds of immune cells; (2) understand mechanisms by which the compounds affect cellular inflammatory responses; (3) evaluate the compounds as potential treatments in rodent models of inflammatory diseases implicated from cell studies. This study is anticipated to lead to clinical studies for a new kind of drug treatment.
Determining Modes Of Binding And Activation Of Peptide G-protein Coupled Receptor Targets
Funder
National Health and Medical Research Council
Funding Amount
$576,538.00
Summary
The neuropeptide relaxin-3 and the peptide hormone INSL5 are recently discovered members of the relaxin peptide family. Relaxin-3 has important roles in stress and feeding whereas INSL5 is a gut hormone. We will study the interaction of relaxin-3 and INSL5 with their cell surface receptors and the mechanisms by which the receptors function. The knowledge gained will aid in the design of smaller, more potent and orally active forms of relaxin-3 and INSL5 for future clinical applications
Signalling Through A Bioactive Aggrecan Fragment: What Is The Mechanism?
Funder
National Health and Medical Research Council
Funding Amount
$431,347.00
Summary
Osteoarthritis (OA) affects approximately 20% of Australians. There are no therapies that modify the course of the disease and joint replacement surgery is expensive and invasive. We have discovered that a peptide product of cartilage breakdown (the 32mer) signals cartilage cells to mount an inflammatory and catabolic response. We will determine how the 32mer triggers this response, whether other joint cells are similarly activated and how it can be stopped, with the goal of pursuing new targets ....Osteoarthritis (OA) affects approximately 20% of Australians. There are no therapies that modify the course of the disease and joint replacement surgery is expensive and invasive. We have discovered that a peptide product of cartilage breakdown (the 32mer) signals cartilage cells to mount an inflammatory and catabolic response. We will determine how the 32mer triggers this response, whether other joint cells are similarly activated and how it can be stopped, with the goal of pursuing new targets for therapyRead moreRead less
A Helminth-derived Peptide Is A Novel Prophylactic And Therapeutic Treatment For Autoimmune Disease
Funder
National Health and Medical Research Council
Funding Amount
$658,778.00
Summary
Parasitic worms (helminths) secrete molecules that possess a remarkable ability to skew the mammalian immune system towards anti-inflammatory responses. We have expoited a novel peptide secreted by helminths, which offers tremendous potential for the development of novel prophylactic and therapeutic treatments for a range of immune-mediated conditions. The overarching aim of this project is to further elucidate the mechanism of action and to determine the peptide’s clinical application.
Unraveling Fibrosis By Pharmacological Targeting Of The G Protein-coupled Receptor, RXFP1
Funder
National Health and Medical Research Council
Funding Amount
$798,618.00
Summary
Peptides, with their high specificity and low toxicity profiles, are highly attractive alternatives to small molecule drugs. H2 relaxin, a peptide hormone, has a strong potential for treating fibrosis. However, the large size of H2 relaxin makes it difficult and expensive to manufacture. Once administered to patients, it is also quickly degraded. We have developed a small anti-fibrotic relaxin peptide, and propose to understand its mechanism of action and improve its therapeutic indices.
Downsizing A Human Protein To Modulate Inflammatory Diseases
Funder
National Health and Medical Research Council
Funding Amount
$516,793.00
Summary
We have discovered how to downsize a human protein to very small molecules with the same activities and potencies. Small changes enable the compounds to powerfully block the actions of the protein. These small molecules are very stable in blood, whereas the protein deactivates in minutes. This project will develop the small molecules into experimental drugs and test them in human cells and proteins, and in rats to evaluate their potential for treating human inflammatory diseases.
Modulation Of Feeding Through Pharmacological Targeting Of The Relaxin-3 Receptor RXFP3
Funder
National Health and Medical Research Council
Funding Amount
$584,955.00
Summary
Relaxin-3 is a neuropeptide that regulates a number of physiological processes, including food intake, suggesting that the relaxin-3 receptor RXFP3 may be a new target for treatment of eating disorders such as obesity. This project will develop new selective and high-affinity ligands for RXFP3, which will be critical pharmacological tools for the preclinical studies and evaluation of this system.
Novel Treatments Of Fibrosis For Hypertensive Heart Disease
Funder
National Health and Medical Research Council
Funding Amount
$912,536.00
Summary
A recognised risk factor for cardiovascular disease is high blood pressure which contributes to a stiffer heart that can ultimately lead to heart failure. There are very few treatments that can reduce heart stiffening, called fibrosis. This project is focused on the preclinical testing of novel compounds that we have developed to reverse the build-up of fibrosis in the heart, which will lead to better treatment of elderly patients with high blood pressure and poorly-functioning hearts.