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Student research project

Novel anti-inflammatory and anti-fibrotic agent for the treatment of heart failure with preserved ejection fraction (HFpEF)

Supervisors: Associate Professor Bing Wang and Professor David Kaye

The underpinning cellular and molecular pathophysiology of heart failure with preserved ejection fraction (HFpEF) are complex. Inflammation is a critical contributor to the pathogenesis of HFpEF, being a key driver of fibrosis. Our team has experience in the use of a range of animal models to study the pathogenesis of cardiac fibrosis and failure including angiotensin II (AngII) mini-pump and high-fat diet studies. Our study demonstrated significant histological features of fibrosis and activation of molecular pathways related to both inflammation and collagen metabolism. To complement these studies, we have characterised the profile of inflammatory cytokines and related markers in HFpEF patients and healthy volunteers using a proteomic-based approach. Given that there is a lack of effective therapy for patients with HFpEF and the critical role that inflammation and fibrosis plays in HFpEF, we have recently developed a novel anti-inflammatory and anti-fibrotic compound, VCP979, that has good efficacy (both in vitro and in vivo), oral bioavailability and pharmacokinetics. This project will investigate the therapeutic potential of VCP979 for the treatment and/or prevention of HFpEF.

Project summary

This project seeks to investigate the therapeutic potential of VCP979 in a mouse model of HFpEF. The animal model to be used features consistent with the HFpEF cardiac phenotype (hypertension, inflammation, cardiac fibrosis, and diastolic dysfunction. HFpEF models will be established by AngII-infusion in mice implanted with mini-pumps (AngII 0.25mg/kg/min, Alzet) over 8 weeks or a high-fat diet fed in mice for 12 weeks. This study will test the ability of VCP979 to both prevent and reverse myocardial fibrosis and inflammation associated with the HFpEF phenotype. Cardiac physiology will be assessed by electrocardiography using VisualSonics Vevo 2100, and by cardiac catheterisation (1.4 Fr Millar catheter) to measure arterial and left ventricular pressures as established in the Baker Heart and Diabetes Institute mouse core facility.

Echocardiography will provide assessments of chamber size, left ventricular function (LVEF) and diastolic function (E/A). Blood pressure during the study will be determined by tail cuff plethysmography. Renal function will be assessed at the end of the study by urine collection in a metabolic cage and creatinine clearance will be calculated from measurement of the plasma and urine creatinine, together with urine volume. Myocardial fibrosis and gene expression: At the conclusion of the study period, myocardial samples will be collected for histology and molecular analyses. Fibrosis will be assessed quantitatively in Massson’s stained sections using an Image J based automated platform.

This project is suitable for a Masters, Honours or PhD student and will involve the application of various techniques including mRNA expression, real-time PCR, histology, Western blots, cell culture, and data analysis.

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