This project aims to create unique small molecules that can bind and activate receptors that are able to reverse fibrosis.
Fibrosis is a state in which excessive extracellular matrix (ECM) deposition replaces healthy muscular tissue leading to progressive deterioration of organ function. This state occurs when collagen synthesis exceeds collagen breakdown by matrix metalloproteinases (MMPs), and is associated with inflammation and recruitment of myofibroblasts which exhibit a marked secretory phenotype causing further ECM deposition, leading to organ failure. In the heart, mechanical (e.g. pressure/ cardiac load), tissue (e.g. ischaemia/infarct) and endocrine (e.g. Ang II, inflammatory cytokines) factors contribute to fibrosis via TGF-B-induced myofibroblast recruitment, with decreased cardiac distensibility, ultimately progressing to heart failure if left unchecked. Moreover, there is a direct link between increased cardiac fibrosis and poor cardiovascular outcome. Fibrosis is therefore a significant condition which has not been adequately treated. We have developed a lead peptide pharmacophore that is able to prevent AND reverse fibrosis in multiple animal models. Therefore, the focus of this PhD program will be to design and synthesise small molecules that are able to mimic the peptide pharmacophore and retain function. This project will require sikills in synthetic organic chemistry and pharmacology.