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
Scleroderma or systemic sclerosis is a debilitating disease that is characterised by fibrosis of multiple organs leading to organ failure and eventually death. There is currently no cure for the disease. We are beginning to find that a newly-discovered class of molecules, called microRNAs, regulate many disease states but its role in scleroderma has not been established. We aim in this study to identify disease-related changes in microRNAs which may subsequently be used as therapeutic targets.
The Structural Basis Of The Interaction Of Human Relaxins With Their Receptors.
Funder
National Health and Medical Research Council
Funding Amount
$489,000.00
Summary
Human Gene 2 (H2) relaxin is a peptide hormone structurally related to insulin and has numerous biological actions related to its roles during pregnancy. It exerts these primarily by inducing the breakdown of collagen and the formation of new blood vessels while simultaneously stimulating tissue growth and inhibiting cell death. Its functions have led to several potential therapeutic roles for relaxin being explored. These include the treatment of fibrotic disorders and peripheral vascular disea ....Human Gene 2 (H2) relaxin is a peptide hormone structurally related to insulin and has numerous biological actions related to its roles during pregnancy. It exerts these primarily by inducing the breakdown of collagen and the formation of new blood vessels while simultaneously stimulating tissue growth and inhibiting cell death. Its functions have led to several potential therapeutic roles for relaxin being explored. These include the treatment of fibrotic disorders and peripheral vascular disease. H2 relaxin is the principal expression product in vivo and has been shown to exert a wide range of physiological responses beyond those normally associated with pregnancy. We have recently discovered another human - H3 - relaxin that is expressed primarily in the brain which strongly suggests a neuropeptide role. Surprisingly, H2 and 3 relaxins each act via different G-protein coupled receptors. We will perform detailed structure-function studies to determine how these relaxins impart their specific biological actions. Modern chemical synthesis protocols will be used to prepare each of these complex peptides in adequate quantities for detailed secondary and tertiary structural study. Analogues containing modified residues and global domains will be prepared and assayed for characteristic relaxin agonist and antagonist activity. Sophisticated biomolecular interaction analyses will be used to identify differences in receptor binding regions for the two relaxins. The results, together with those obtained by three-dimensional structural analysis using NMR spectroscopy, will allow us to ultimately define the key features of the H2 and 3 hormones that are responsible for selective receptor binding and specific relaxin activity. We will then be able to design smaller, more stable, orally active relaxin mimetics. Such compounds will have great potential for therapeutic application in the treatment of fibrosis or as biological and pharmacological probes of relaxin action.Read moreRead less
The Structural Basis Of The Interaction Of Human Relaxins With Their Receptors.
Funder
National Health and Medical Research Council
Funding Amount
$573,807.00
Summary
Relaxin is a peptide that is involved in the regulation of the birth process. It has considerable promise as an anti-fibrotic agent. Recently, another relaxin-like peptide, relaxin-3, was identified and shown to be brain-specific. It modulates the stress response and appetite. Both relaxins act upon different receptors to elicit their biological effects. To exploit their clinical potential, we will determine how these peptides selectively bind and ativate their individual receptors.
Targeting The Pathophysiology And Therapy Of Liver Fibrosis
Funder
National Health and Medical Research Council
Funding Amount
$484,006.00
Summary
Hepatic fibrosis, or scarring of the liver, is a serious condition which can lead to liver cancer or death. Treatment of liver scarring is currently not effective once the scarring is well developed. This project aims to examine agents which may act to halt liver scarring once it has already developed. Outcomes from this project may help provide potential treatments to reduce the need for liver transplantation or to reduce patient deaths.
Aberrant Signalling Through Gp130 In The Pathogenesis Of Fibrotic Lung Diseases
Funder
National Health and Medical Research Council
Funding Amount
$456,500.00
Summary
Pulmonary fibrosis is a chronic diffuse interstitial lung disease of unknown cause, characterised pathologically by inflammation and fibrosis of the lung tissue. The prognosis is poor with a 50% mortality at five years after diagnosis and considerable morbidity during those years. Previous investigations have documented the role for inflammation in the development of pulmonary fibrosis and current therapeutic strategies are aimed at suppressing the inflammation. Data generated over the past deca ....Pulmonary fibrosis is a chronic diffuse interstitial lung disease of unknown cause, characterised pathologically by inflammation and fibrosis of the lung tissue. The prognosis is poor with a 50% mortality at five years after diagnosis and considerable morbidity during those years. Previous investigations have documented the role for inflammation in the development of pulmonary fibrosis and current therapeutic strategies are aimed at suppressing the inflammation. Data generated over the past decade also have established the concept that the molecular processes underlying the fibrogenesis component may represent a new opportunity for therapeutic intervention. Attempts to treat fibrosis have for the most part consisted of anti- inflammatory drugs, almost exclusively steroids. The effectiveness of steroids is variable and can be associated with significant side effects. This project will examine the effects of a family of molecules called cytokines that signal through gp130 as critical determinants of disease susceptibility and progression. gp 130 is a shared component in the receptor complexes for IL-6 family cytokines (IL-6, IL-11, LIF, OSM) which are important regulators of both the phenotype and proliferation of fibroblasts in health and in response to injury. Our data raises the possibility of developing pharmacological manipulators of gp130 signalling pathways that would suppress fibrosis but leave normal cellular defense mechanisms necessary for host defense in the lung intact.Read moreRead less
The Role Of The Adiponectin Receptors In Liver Fibrosis
Funder
National Health and Medical Research Council
Funding Amount
$393,159.00
Summary
Advanced liver scarring (fibrosis) contributes to the death of 1500 Australians annually. Two-thirds of our community is overweight or obese, and this worsens liver disease. A protein secreted by fat, adiponectin, may be important as it acts on liver cells to promote fibrosis. To understand adiponectins role, we will use mice null for adiponectin receptor genes and study its action on liver cells. This study will improve our understanding of liver scarring biology and patient treatments.
THE ROLE OF THE HEPATOCYTE IN EXTRACELLULAR MATRIX INTERACTIONS IN LIVER FIBROGENESIS
Funder
National Health and Medical Research Council
Funding Amount
$540,438.00
Summary
This study focuses on the main cell within the liver, the hepatocyte, and its role in the development of liver fibrosis. Liver fibrosis arising from liver injury has a common progression characterised by loss of liver structure and the development of dense fibrous bands of tissue in the condition known as cirrhosis. The importance of the outlined research plan is that for the first time the hepatocyte has been identified as having a significant role in the development of liver fibrosis.
Pre-clinical Development Of A Novel Anti-fibrotic, Anti-inflammatory Compound To Treat Diabetic Heart Disease
Funder
National Health and Medical Research Council
Funding Amount
$488,391.00
Summary
Diabetic patients are prone to developing chronic heart failure. In the diabetic heart, scar tissue accumulates within the muscle (fibrosis), impairing function. We have developed a new drug to treat fibrosis in diabetic kidney disease (FT-11), and have approval for pre-clinical development of this drug. We now aim to test whether FT-11 is also effective in reducing fibrosis in the diabetic heart, and whether this can prevent heart failure in an animal model of diabetic heart disease.