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Student research project

Supervisors: Associate Professor David Greening and Associate Professor Bing Wang

Project summary

Cardiovascular disease (CVD) includes heart, stroke, and blood vessel diseases, and is the leading cause of death worldwide. In Australia, CVD accounts for 27% of all deaths and one in five Australians over the age of 40 has a high risk of developing cardiac damage. CVD deeply affects patient’s physical condition, mental health, and life expectancy and cost billions of dollars to the society. This major public health issue needs to be addressed by advancing research on the understanding of the cellular and molecular changes occurring in the damaged heart known as cardiac remodelling. Such pathogenic remodelling leads to abnormalities in extracellular matrix composition and directly impairs cardiac function. In hypertensive hearts, cardiac fibrosis (CF) manifests as interstitial fibrosis accumulating between cells, which results in stiffening of the cardiac tissue, perturbing cardiac function and promoting the development of HF.

The past few decades have witnessed transformative progress in understanding cardiac remodelling and treatment of myocardial disease, including small molecule inhibitors, biologicals, implantable devices, and heart transplantation. Current therapies improve myocardial performance and blood supply but do not halt or reverse progression completely. Well established approaches modifying cell biology by receptor blockade are evolving, exploring the role and impact of modulating intracellular signalling pathways as an opportunity to treat CF. Small molecule inhibitors VCP979 and G2261818A (G226) have been shown to improve pathological myocardial fibrosis both by inhibiting the inflammatory response and suppressing p38-MAPK, a crucial player in the Ang II/TGFβ signalling. MIPS247 has also shown an anti-fibrotic activity by inhibiting collagen synthesis, partly via PI3 kinase/phosphatase and tensin homolog pathway. However, the cellular remodelling and signalling underlying these molecules activity remains unknown.

This proposal will focus on investigating the global proteome and phosphorylation signalling landscape following novel anti-fibrotic treatments of cardiac fibroblasts. Using state-of-the-art high-resolution mass spectrometry, phosphorylation signalling, integrated informatics, and cell biology will understand pathophysiological mechanisms in cardiac fibroblasts. This work will bring a unique understanding of dynamic key signalling pathways that contribute to drug-based treatment of pathological cardiac remodelling.

This project is suitable for a Master or PhD student.

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