Epigenetic modifications in Dupuytren's diseases

Fibrosis, a hallmark of many clinical disorders, occurs because of uncontrolled cellular activity. Dupuytren's disease (DD) is a very common progressive fibrosis of the palm leading to flexion deformities of the digits that impair hand function and significantly diminish quality of life. The cell likely responsible for development of DD is the myofibroblast. There is currently limited treatment for early DD or for preventing recurrence following surgical excision of affected tissue in advanced disease. This project will provide key insights into the mechanisms behind how the myofibroblast cell responsible goes about causing the hand tissue to contract. Importantly analysis of the cell pathways involved in this process may allow us to repurpose drugs used in other conditions to help treat DD and other fibrotic conditions

Despite the frequency of its occurrence (prevalence >7% in the USA), Dupuytren's Disease (DD) of the hand has received limited attention to date. DD pathogenesis likely involves several inflammatory and fibrotic molecular pathways that are already characterised in other contexts, and thus a broad array of potential targets for drug development and early diagnostic markers likely exist. As such, it provides a good example of the challenge faced by researchers attempting to unravel molecular mechanism in common diseases of underappreciated functional impact. While a helpful nonsurgical treatment for symptoms of the DD has recently become available, the molecular mechanisms that lead to its emergence are not understood. Our preliminary data suggest that an epigenetic modification driving aberrant tissue fibrosis offers a potential for therapeutic manipulation of DD. relevant disorders across broader clinical fibrosis domains. We propose a feasible programme of preclinical work using existing methodologies, preclinical tool compounds and laser capture methods. The readouts in vitro and ex vivo are clear and will allow a milestone driven approach as envisaged in EMINENT programmes. We propose this as a preclinical project that if successful has potential to identify new targets and may allow repositioning of existing drugs to treat DD.