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Developing novel therapies for fibrosis

Description 
Fibrosis is defined as the hardening and/or scarring of various organs including the heart and kidney, which usually results from abnormal wound healing to tissue injury, resulting in an excessive deposition of extracellular matrix components, primarily collagen. The eventual replacement of normal tissue with scar tissue leads to organ stiffness and ultimately, organ failure. Despite a number of available treatments for patients with various heart/kidney diseases, patients receiving these therapies still progress to end-stage organ failure due to the inability of these treatments to directly target the build-up of fibrosis. Hence, novel and more direct anti-fibrotic therapies are still required to be established. The Fibrosis Lab focuses developing several peptide and stem cell-based anti-fibrotic therapies – which include: The hormone relaxin: Which is mainly produced in the ovary of pregnant mammals, the prostate and testes of males as well as a number of non-reproductive organs. As a recombinantly-produced drug-based form, it has a number of beneficial effects in the body including an ability to prevent inflammatory reactions, tissue fibrosis, oxidative stress and cell death, vasoconstriction of blood vessels and organ hypertrophy, while promoting angiogenesis and blood vessel growth in addition to stem cell survival. Angiotensin peptide mimetics and inhibitors: In collaboration with Prof. Robert Widdop (Monash Pharmacology), we are evaluating more selective mimetics acting at the angiotensin type 2 (AT2) receptor (which forms part of the protective arm of the renin-angiotensin-system). Additionally, we are evaluating inhibitors of insulin-regulated aminopeptidase (IRAP) activity in experimental models of heart and kidney disease. The anti-fibrotic effects of these mimetics/inhibitors are being compared to ACE inhibitors and angiotensin receptor blockers (which represent current standard of care). Combining relaxin with stem cell-based therapies: It has emerged that fibrosis/scar formation limits stem cell homing, proliferation and overall viability, while forming a barrier against the proper integration of implanted stem cells with resident native cells. Thus, interventions that favourably reduce fibrotic healing may benefit stem cell-based therapies in chronic disease settings. In collaboration with Prof. Sharon Ricardo (Monash Anatomy) and Dr Rebecca Lim (Hudson Institute), we have recently demonstrated that the anti-fibrotic effects of relaxin augment the therapeutic and tissue-repairing properties of human bone marrow-derived mesenchymal stem cells (Huuskes B et al., FASEB J 2015; 29:540-53; Royce S et al., Stem Cell res 2015; 15:495-505) or human amnion epithelial cells (Royce S et al., Clinical Science 2016; 130:2151-65). Several studies have shown that these anti-fibrotic compounds/mimetics/strategies prevent and/or reverse fibrosis in various experimental models of heart and kidney disease (fibrotic cardiomyopathy, hypertension, myocardial infarction, diabetic cardiomyopathy, tubulointerstitial renal fibrosis) regardless of etiology. This is achieved through their ability to disrupt transforming growth factor (TGF)-beta 1 activity (the major pro-fibrotic factor that promotes collagen production and scar tissue accumulation) and/or being able to augment matrix metalloproteinase (MMP) activity (which are enzymes that mediate the breakdown of collagen). However, further work, which will form the basis of potential Masters and PhD projects requires 1) an investigation of the signal transduction pathways by which these compounds/mimetics/strategies mediates their anti-fibrotic actions - to identify novel therapeutic targets that may be utilised to enhance its anti-scarring actions; and 2) comparing the anti-fibrotic actions of these compounds/mimetics/strategies to currently available therapies such as ACE inhibitors, angiotensin receptor blockers and aldosterone receptor blockers - to demonstrate their effectiveness as suitable replacement or adjunct anti-fibrotic therapies.
Essential criteria: 
Minimum entry requirements can be found here: https://www.monash.edu/admissions/entry-requirements/minimum
Keywords 
Fibrosis, Extracellular matrix, Cardiovascular disease, Kidney disease, Lung disease, Stem cell biology, Department of Pharmacology
School 
Available options 
PhD/Doctorate
Masters by research
Time commitment 
Full-time
Top-up scholarship funding available 
No
Physical location 
Biomedicine Discovery Institute

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