Improving Outcomes And Cost Of Systemic Sclerosis Related Pulmonary Arterial Hypertension
Funder
National Health and Medical Research Council
Funding Amount
$645,205.00
Summary
My research program aims to improve the outcomes for those living with systemic sclerosis related pulmonary arterial hypertension (SSc-PAH) and reduce its associated societal burden through the evaluation and implementation of a novel PAH screening algorithm; the use of risk stratification tools in therapeutic decisions; and the development of a more streamlined management approach. My research will initiate collaboration across multiple medical disciplines and sites nationally.
NOVEL NON-INVASIVE METHODS FOR THE EARLY DETECTION OF PULMONARY VASCULAR DISEASE
Funder
National Health and Medical Research Council
Funding Amount
$320,463.00
Summary
Pulmonary arterial hypertension (PAH) is a severe, progressive disorder. Current non-invasive diagnostic modalities are insensitive for detecting early disease, thus preventing early intervention with therapy. We aim to develop novel and reproducible ways to assess the pulmonary circulation, which will ultimately allow for the early diagnosis of PAH and in turn facilitate early initiation of treatment and improved patient outcomes.
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.
Optimising Accuracy And Cost-Effectiveness Of Screening For Pulmonary Arterial Hypertension In Scleroderma
Funder
National Health and Medical Research Council
Funding Amount
$375,403.00
Summary
Scleroderma is one of the most devastating diseases of the immune system. With features that affect every organ in the body, scleroderma shortens the average patient’s life by over three decades. Pulmonary arterial hypertension (PAH), a condition of increased resistance in the blood vessels of the lungs, is the major cause of death in this disease. The purpose of this project is to develop a new 'screening' model for the early detection of PAH in scleroderma, thereby enabling earlier initiation ....Scleroderma is one of the most devastating diseases of the immune system. With features that affect every organ in the body, scleroderma shortens the average patient’s life by over three decades. Pulmonary arterial hypertension (PAH), a condition of increased resistance in the blood vessels of the lungs, is the major cause of death in this disease. The purpose of this project is to develop a new 'screening' model for the early detection of PAH in scleroderma, thereby enabling earlier initiation of life-saving treatment.Read moreRead less
Risk Factors For The Development Of Pulmonary Arterial Hypertension In Systemic Sclerosis: A Prospective Cohort Study
Funder
National Health and Medical Research Council
Funding Amount
$87,199.00
Summary
I am a rheumatologist treating systemic sclerosis, a life threatening illness. A serious complication is high blood pressure in the lungs, or pulmonary arterial hypertension. Unfortunately this problem is often detected too late. My goal is to be able to identify those patients who will develop this condition so that they can access life saving treatment at the earliest possible time in order to improve their quality of life and increase their chance of survival.
Improving Outcomes In Systemic Autoimmune Disease: A Collaborative And Interdisciplinary Program Of Research
Funder
National Health and Medical Research Council
Funding Amount
$425,048.00
Summary
The multi-organ autoimmune diseases ‘scleroderma’ and ‘lupus’ have a profound negative impact on quality of life and life expectancy. The overall goal of my research is to improve patient outcomes in these two diseases. My collaborative and interdisciplinary research program entails quantifying disease burden, identifying patient subsets, optimising screening for complications, developing outcome measures for use in practice and research, and trialing new therapies.
Quantifying The Burden Of Systemic Sclerosis In Australia: From Data Linkage To Patient Reported Outcomes
Funder
National Health and Medical Research Council
Funding Amount
$81,976.00
Summary
Systemic sclerosis (SSc) is a rare autoimmune disease with the potential to cause significant physical, financial and psychosocial burden on patients, their family members and wider community. The true ‘burden’ of SSc in Australia is unknown. My study aims to quantify this burden of disease and use our results to advocate for appropriate allocation of resources with the ultimate goal of improving patient outcomes and reducing the financial and human costs of this chronic rare disease.