Preclinical testing of collagen synthesis inhibitors for fibrotic disease

Description

Fibrotic disease is characterised by an excessive accumulation of collagen within tissues, which then impedes tissue function. Organ fibrosis specifically kidney fibrosis, liver fibrosis, cardiac fibrosis and lung fibrosis have limited treatment options, pose a huge clinical burden and are life-limiting diseases. Fibrosis also occurs more peripherally in skin in scleroderma, can occur as a result of radiotherapy (radiation-induced fibrosis) and presents in the palmar fascia of the hands of patients with Dupuytren’s disease. Dupuytren’s fibrosis is often treated surgically by excision of the fibrotic tissue (Layton et. al. 2022), hence provides an accessible tissue source to study collagen deposition in fibrotic disease.

Dupuytren’s disease is itself painful and debilitating for patients, who can face amputation of one or more digits in severe cases. Treatment is complicated by recurrence following surgery in many cases. Recent advances have included testing the anti-TNF biologic adalimumab to reduce progression in early stage disease, with promising results (Nanchahal et. al. 2022). Our recent work has however shown that anti-TNF does not largely reduce collagen production (Williamson et. al., 2023), hence alternative strategies may be of benefit for patients.

In a recently completed study we tested 10 cytokine/pathway inhibitors in Dupuytren’s tissue and Dupuytren’s cultured cells and identified one inhibitor with the potential to block over-production of collagen. As the inhibitors were tested in a design involving co-treatment with 2 or more inhibitors the next step is to perform tests using our lead inhibitor alone, to perform parallel studies on cell viability and to test related inhibitors of the same cytokine/pathway to improve specificity and reduce off-target effects.

The objectives of this PhD project are therefore:

1. To test how inhibitors of the identified cytokine/pathway influences collagen production and cellular viability, in cells derived from Dupuytren’s tissue in standard 2D culture, and compared to healthy control cells.
2. To test the effectiveness of inhibitors of the identified cytokine/pathway in a 3D culture comprising cell-derived collagen fibrils.
3. To use the inhibitors of the identified cytokine/pathtway in Dupuytren’s and control tissue explants and determine a suitable treatment time.

Training will be provided in techniques required for the project including cell culture, bioengineering of 3D cultures, viability assays, metabolic labelling, SDS Page, histology and human tissue handling. The research group has experience with handling Dupuytren’s tissue and cells and with the required assays for the project.

This project has the potential to verify a new inhibitor for Dupuytren’s fibrosis and to identify a suitable pathway for targeting with applications in skin and organ fibrosis.

Applications will close when a suitable candidate is appointed. The deadline may therefore be subject to change.

To apply: please send your CV and a covering letter to Dr Elizabeth Laird elizabeth.laird@liverpool.ac.uk