NOVEL CGMP-BASED THERAPIES PREVENT LEFT VENTRICULAR REMODELLING
Funder
National Health and Medical Research Council
Funding Amount
$533,433.00
Summary
Over 300,000 Australians are affected by heart failure. Current drugs for cardiac remodelling (the decline in heart pumping function and changed structure that precede heart failure) slow but not reverse disease progression. We have identified a new, nitrovasodilator-based therapy superior to those currently available. We propose it represents a more effective treatment for reversing abnormalities in both structure and function in the remodelled heart, preventing or delaying heart failure.
TARGETING ROS-INDUCED DAMAGE RESCUES THE DIABETIC HEART
Funder
National Health and Medical Research Council
Funding Amount
$487,669.00
Summary
Over 1 million Australians have diabetes. Many of these patients die from cardiovascular disease. We have identified free radicals as a major cause of decreased pumping function and impaired recovery from each heartbeat in the diabetic heart. Stronger antioxidant approaches and-or activation of protective protein pathways is a more effective treatment for reversing impaired function in the diabetic heart, preventing or delaying heart failure in patients with diabetes.
Novel G-protein Coupled Receptors LGR7 And LGR8; The Receptors For Relaxin And Insulin-like Peptide 3 (INSL3)
Funder
National Health and Medical Research Council
Funding Amount
$496,500.00
Summary
Relaxin is a hormone which has long been known to have essential roles in pregnancy and birth. However it has also been demonstrated to have far broader involvement in the functioning of the kidney, heart and central nervous system. Furthermore, mice lacking relaxin show increased collagen, or fibrosis, in their internal organs and skin as they age. This progressive fibrosis leads to problems with bodily functions. Treatment of these mice with relaxin reverses the fibrosis and restores function, ....Relaxin is a hormone which has long been known to have essential roles in pregnancy and birth. However it has also been demonstrated to have far broader involvement in the functioning of the kidney, heart and central nervous system. Furthermore, mice lacking relaxin show increased collagen, or fibrosis, in their internal organs and skin as they age. This progressive fibrosis leads to problems with bodily functions. Treatment of these mice with relaxin reverses the fibrosis and restores function, hence relaxin has great potential as a treatment for fibrotic diseases. Anti-fibrotic drugs are a major target for drug companies as suitable compounds are not currently available. Research into the mechanisms whereby relaxin exerts its cellular effects has been limited by the inability of researchers to identify its receptor. We now know that relaxin acts through a novel G-protein coupled receptor (GPCR) LGR7 and will also act on a related receptor LGR8. The LGR8 receptor is actually the receptor for a hormone with similarities to relaxin, INSL3. It is essential that an appreciation of relaxin receptor function is obtained not only for its important actions in pregnancy, but also for its clinical applications. In this regard, improved understanding of how relaxin interacts with these two receptors is essential. We will use our expertise in producing these hormones together with molecular techniques to produce the receptor, to study the interaction of relaxin and INSL3 with these receptors and the subsequent cellular events that occur. Furthermore, to more effectively use relaxin as a drug, we need to discover a smaller, more potent and orally active form of the hormone. We will develop novel technologies to aid in the discovery of the next generation of relaxin drugs. This multi-disciplinary approach will allow us to fully maximise the clinical potential of this enigmatic hormone.Read moreRead less
Impact Of Airway Wall Fibrosis On The Efficacy Of Anti-asthma Drugs
Funder
National Health and Medical Research Council
Funding Amount
$432,750.00
Summary
Most episodes of asthma are controlled or prevented by current medications. In a small, but significant proportion of asthmatics (5-10%) symptoms persist despite the use of the best combinations of anti-asthma drugs. One of the reasons that acute episodes of asthma occur is that the airway tubes slowly change in structure. These changes involve an increase in the amount of collagen (part of the cement between cells) making the airway stiffer. In this project, we are exploring the impact of the s ....Most episodes of asthma are controlled or prevented by current medications. In a small, but significant proportion of asthmatics (5-10%) symptoms persist despite the use of the best combinations of anti-asthma drugs. One of the reasons that acute episodes of asthma occur is that the airway tubes slowly change in structure. These changes involve an increase in the amount of collagen (part of the cement between cells) making the airway stiffer. In this project, we are exploring the impact of the stiffening of the airway on the way that different cells within the airway wall respond to drugs used to treat asthma. Our initial findings suggest that when the airway wall becomes stiffer with more collagen, there is a diminished benefit from the anti-asthma drugs. This new study is designed to identify the molecular mechanisms for the poor response to the anti-asthma drugs. With this knowledge it will be easier to design and test new drugs that are more effective in severe asthma.Read moreRead less
Epithelium-fibroblast Interactions In Response To Allergic Airway Inflammation
Funder
National Health and Medical Research Council
Funding Amount
$235,526.00
Summary
The airways of an asthmatic patient undergo dramatic structural changes over time. This remodelling is thought to be responsible for producing the changes in lung function that are frequently observed in someone with the disease. However, in contrast to normal wound repair, it is unclear why in the majority of asthmatics, inflammation leads to ongoing remodelling rather than a self limiting healing process. In this context, cells that line the airways (epithelium) as well as cells that sit immed ....The airways of an asthmatic patient undergo dramatic structural changes over time. This remodelling is thought to be responsible for producing the changes in lung function that are frequently observed in someone with the disease. However, in contrast to normal wound repair, it is unclear why in the majority of asthmatics, inflammation leads to ongoing remodelling rather than a self limiting healing process. In this context, cells that line the airways (epithelium) as well as cells that sit immediately beneath them (fibroblasts) are important sources of mediators and structural matrix proteins that contribute to these processes. Under normal conditions, signals from these structural proteins are transmitted to the cells via specific adhesion molecules. However, in asthma epithelial cells are frequently damaged and detached, and fibroblasts appear to proliferate and undergo changes in their appearance. This projects aims to investigate the expression and function of specific cell adhesion molecules in the epithelium and fibroblasts following airway inflammation. Specifically, this proposal aims to determine which adhesion molecules are associated with upregulated proliferation and production of matrix proteins. We will also examine the effects of two novel mediators, thought to play a role in remodelling on the expression and function of these adhesion molecules. Proliferation of these cells and the altered deposition of matrix proteins may be a key feature of airway wall thickening and hyperreactivity that is a characteristic feature of asthma. The balance of deposition and breakdown of matrix proteins is regulated by a variety of mediators. Defining what regulates the expression and activity of adhesion molecules is of fundamental importance in determining how the normal repair processes may evolve into airway wall remodelling.Read moreRead less
Novel Actions Of Beta-adrenoceptor Antagonists: Implications For The Treatment Of Cardiac Failure
Funder
National Health and Medical Research Council
Funding Amount
$142,630.00
Summary
Almost 2-3 of drugs on the market act on G protein-coupled receptors, and many are antagonists that block receptors. Antagonists were seen as inert compounds that prevent access of natural neurotransmitters or hormones, but recent studies indicate distinct actions. We believe that atypical effects of beta-adrenergic antagonists may explain their usefulness in treating cardiac failure. We seek to understand the process and develop assays to aid the development of new drugs for cardiac failure.