Fibrosis Laboratory

Team Leader:

Dr Chrishan S. Samuel, PhD (Senior Research Fellow)

Contact details:

Email: chrishan.samuel@monash.edu
Phone: +61 3 9902 0152
Facsimile: +61 3 9905 2547

Research Interests:

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 on the anti-fibrotic actions of the naturally occurring, 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 - and 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. Several studies have shown that relaxin prevents 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. The hormone achieves its actions by disrupting transforming growth factor (TGF)-1 activity (the major pro-fibrotic factor that promotes collagen production and scar tissue accumulation), while augmenting matrix metalloproteinase (MMP) activity (which are enzymes that mediate the breakdown of collagen).

However, further work, which will form the basis of potential honours projects requires 1) an investigation of relaxin signal transduction pathways by which it mediates its anti-fibrotic actions - to identify novel therapeutic targets that may be utilised to enhance its anti-scarring actions; and 2) comparing its anti-fibrotic actions to currently available therapies such as ACE inhibitors, angiotensin receptor blockers and aldosterone receptor blockers - to demonstrate its effectiveness as a suitable anti-fibrotic and/or adjunct therapy.

Available Projects:

1. Relaxin signal transduction studies
We have recently shown that relaxin activation of its G-protein coupled receptor, RXFP1, initiates a sequence of events involving nNOS-NO-cGMP to disrupt Smad2 phosphorylation (a regulatory protein that promotes TGF-1 activity), and hence, the fibrosis-promoting actions of TGF-1 (Mookerjee I et al., 2009 FASEB J 23:1219-1229).
Using primary human and/or rat fibroblast cultures (collagen producing cells which naturally express RXFP1) and pharmacological inhibitors to various signal transduction pathways - additional pathways by which relaxin signals through to disrupt the actions of TGF-1 and increase MMP activity will be studied. In particular, the angiotensin II, NADPH oxidase and inflammatory pathways (which are all involved in promoting TGF-1 activity) will be investigated.

2. Relaxin efficacy studies
Relaxin is a rapidly-occurring but safe anti-fibrotic, that prevents and/or reverses fibrosis in various experimental models of heart and kidney disease (reviewed in Samuel CS et al. 2006 Pharm Therap 112:529-552; Du XJ et al. 2010 Nat Rev Cardiol 7:48-58).

To further demonstrate its effectiveness as a suitable anti-fibrotic and/or adjunct therapy, the actions of relaxin will be compared to or added to currently used therapies for patients with heart/kidney disease (ACE inhibitors, angiotensin receptor blockers or aldosterone receptor blockers) - in models of ischemic heart disease and obstructed kidney disease; which undergo fibrosis progression in the absence of blood pressure changes.

3. The influence of ageing and gender on fibrosis
Male, but not female relaxin knockout mice undergo an age-related progression of cardiac (Du XJ, Samuel CS et al. 2003 Cardiovasc Res 57:395-404) and renal (Samuel CS et al. 2004 Kidney Int 65:2054-2064) fibrosis; which provides a model to study why men are more prone to heart and kidney disease compared to women.

Using aged and injury-induced relaxin, aromatase and/or androgen receptor knockout mice, the interaction between relaxin, estrogen and testosterone will be further studied to delineate the contributions of each hormone to disease/fibrosis progression.

Laboratory Techniques:

• Animal surgery/pathophysiology
• Functional studies
• Cell culture
• Protein Biochemistry
• Molecular Biology
• Histology/immunohistochemistry