Pathological fibrotic scarring of the skin affects >100 million people every year and conditions related to organ fibrosis contribute to 45% of death worldwide. Fibrotic progression is believed to be crucially influenced by coupled alterations in biophysics of the collagen-rich skin extracellular matrix (ECM) and fibroblast behaviour [1,2], but the fundamental mechanisms have not been quantified. Understanding these mechanisms will help develop effective targeted therapies for fibrosis (none exist yet) and new biomarkers for early detection. Our interdisciplinary supervisory team has shown how high-brilliance synchrotron X-ray imaging can uncover the biophysical response of the collagen fibrillar network in the ECM [3,4] and an unprecedented heterogeneity in fibroblast response in fibrosis .
Using state-of-the-art mechano-structural imaging, the PhD student will investigate the ECM biophysics and fibroblast behavior in regenerating skin, with an unprecedented molecular resolution which will enable new anti-scarring therapies. The project will test the hypothesis that the ECM biophysics fundamentally controls the biological fibroblast response in wound regeneration and scarring.
The project objectives are:
- To visualize the nano-scale biophysical dynamics in the collagen ECM network in regenerating and scarring wounds using synchrotron X-ray imaging and nanoindentation
- To dissect the different fibroblast repair responses to identified ECM biophysical changes/patterns via correlative imaging
- To correlate the observed biophysical and biological changes to develop models to help develop new biomarkers and therapies for fibrotic disorders
Regenerating and scarring skin wounds will be obtained from a well-established mouse model (Rognoni lab) . Synchrotron small-angle X-ray scattering (SAXS) [3,4], at Diamond Light Source, will be used to reveal ultrastructural biophysical interactions of the collagen fibrillar network – both internally (via crosslinking) and externally (with other ECM proteins) – as markers of nanoscale mechanical differences that characterize scarring or regenerative ECM. These measurements will be complemented by lab-based nanoindentation probes to measure local matrix biomechanics. Immunofluorescence confocal microscopy of regenerating and scarring wound skin sections will measure fibroblast density/cytoskeleton organisation, myofibroblast differentiation, cell state (proliferation/senescence/apoptosis) and ECM-remodelling/deposition on the same sample set and same locations used for the biophysical analyses. The identified changes in ECM biophysics will be correlated to biological signals of the cellular response, to develop differentiated biomarkers for fibrotic alterations (scarring skin) versus regeneration (healing wounds).
The project will involve biophysical characterisation using imaging (including X-ray and scanning probe techniques), tissue biomechanics, biochemistry and cell imaging, and analysis techniques using Python code to correlate these measurements in a bioengineering framework. Skills in some or all of these areas are especially welcome, but not essential.
References:  JHW Distler et al, Nat. Rev. Rheumatol. (2019)  A Santos et al, Curr. Rheumatol. Rep. (2018)  SR Inamdar et al, Acta Biomater. (2021)  SR Inamdar et al Acta Biomater. (2019)  E Rognoni et al. Development (2016)  E Rognoni et al Mol. Syst. Biol. (2018)
This studentship is fully funded via the UKRI EPSRC Doctoral Training Programme for 3.5 years and includes a stipend (currently £17,609 in 2021/2022) and Fees.
This year UKRI announced that there will be a limited number of studentships for international students available. International applicants are encouraged to apply but should note that studentship awards will be subject to eligibility and the availability of funding.
To be classed as a home student, applicants must meet the following criteria:
- Be a UK National (meeting residency requirements), or
- Have settled status, or
- Have pre-settled status (meeting residency requirements), or
- Have indefinite leave to remain or enter
If a candidate does not meet the criteria above, they would be classified as an international student.
Further guidance on UKRI Eligibility Criteria is here, and within Annex One of the International Eligibility Guidance.
- The minimum requirement for this studentship opportunity is a good Honours degree (minimum 2(i) honours or equivalent) or MSc/MRes in a relevant discipline.
- If English is not your first language, you will require a valid English certificate equivalent to IELTS 6.5+ overall with a minimum score of 6.0 in Writing and 5.5 in all sections (Reading, Listening, Speaking).
- Candidates are expected to start from September 2022
Supervisor Contact Details:
For informal enquiries about this position, please contact Dr. Himadri S. Gupta (principal supervisor) or Dr. Emanuel Rognoni (second supervisor)
E-mail: [Email Address Removed] (Dr. Gupta) or [Email Address Removed] (Dr. Rognoni)
To apply for this studentship and for entry on to the PhD Full-time Medical Engineering - Semester 1 (September Start) please follow the instructions detailed on the following webpage:
Research degrees in Engineering: http://www.qmul.ac.uk/postgraduate/research/subjects/engineering.html
Further Guidance: http://www.qmul.ac.uk/postgraduate/research/
Please be sure to include a reference to ‘2022 EPSRC DTP HSG’ to associate your application with this studentship opportunity.