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Investigation of the generation of force by fibroblasts under the influence of therapeutic ultrasound

  • Full or part time
  • Application Deadline
    Wednesday, January 23, 2019
  • Self-Funded PhD Students Only
    Self-Funded PhD Students Only

Project Description

"Chronic ulcers are non-healing wounds that affect 200,000 UK patients annually and frequently result in amputation. Although the hallmarks of chronic wounds are chronic inflammation and inactivation of skin fibroblasts, current therapies combat infection but fail to promote the healing process by activating fibroblasts. During healthy healing, fibroblasts migrate to the wound bed, differentiate into myofibroblasts and apply force to contract the wound. The differentiation of fibroblasts and reorganisation of extracellular matrix in the skin has the benefit of quickly narrowing the wound, but the disadvantage of creating a scar. Ideally we would like to achieve rapid, scar-free healing. We recently published that delayed skin healing could be accelerated using ultrasound stimulation. Surprisingly, we found that, despite enhancing wound contraction, ultrasound inhibited differentiation into myofibroblasts. Fibroblasts can apply force by reorganisation of skin collagen, or adapting in their cytoskeleton through changes in actin expression, myosin expression or myosin activity through phosphorylation. Achieving rapid wound closure without full differentiation could allow scar-free healing to be achieved, and the challenge is discovering how contraction is achieved without differentiation.

The aim of your project will be to examine the effect of ultrasound on the fibroblast contractility and composition of the extracellular matrix. For the first part you will examine potential changes in the cytoskeleton of treated fibroblasts using biochemical techniques to test the effect on expression and phosphorylation of actins and myosins. Changes are more likely to occur at the organisational than expression levels, so you will generate images of the cytoskeleton of stimulated cells and use in-house software algorithms to analyse the organisation of cytoskeletal filaments. You will also examine the effect on cytoskeletal reorganisation in real time using video microscopy. For the second part of the project, you will look at the composition and structure of secreted matrix. You will use qPCR to detect ultrasound-dependent changes in expression of matrix proteins, backed up by blotting analysis. You will generate synthetic skin either in the presence or absence of ultrasound and use our algorithms to detect changes in matrix structure before investigating matrix crosslinking. Together, these experiments will determine relative contributions of cell contractility and matrix reorganisation, determine the molecular basis of ultrasound-stimulated wound contraction and ascertain how ultrasound is likely to affect scarring. Finally, the two parts of the project will be drawn together by using traction force microscopy to measure the effect of ultrasound on contractility directly.

Overall this project will provide training in a range of broadly used and specialised techniques and answer a question that is likely to lead to development of new healing therapies. Working alongside our existing therapy development, you will gain experience in both mechanistic and translational cell biology, and expertise in taking a project from basic science to clinical impact.

Science Graduate School
As a PhD student in one of the science departments at the University of Sheffield, you’ll be part of the Science Graduate School. You’ll get access to training opportunities designed to support your career development by helping you gain professional skills that are essential in all areas of science. You’ll be able to learn how to recognise good research and research behaviour, improve your communication abilities and experience the breadth of technologies that are used in academia, industry and many related careers. Visit http://www.sheffield.ac.uk/sgs to learn more.
"

Funding Notes

Please note that we have a number of fee scholarships available, please get into contact with Dr. Kai Erdmann in case you would like to know more: View Website

Entry requirements
First class or upper second 2(i) in a relevant subject. To formally apply for a PhD, you must complete the University's application form using the following link: View Website
*All applicants should ensure that both references are uploaded onto their application as a decision will be unable to be made without this information*.

References

"Roper, Williamson, Bally, Cowell, Brooks, Stephens, Harrison, Bass. (2015) Ultrasonic stimulation of mouse skin reverses the healing delays in diabetes and aging by activation of Rac1. J Invest Dermatol. 135: 2842.
http://www.ncbi.nlm.nih.gov/pubmed/26079528

Cash, Bass, Campbell, Barnes, Kubes, Martin. (2014) Resolution mediator Chemerin15 reprograms the wound microenvironment to promote repair and reduce scarring. Current Biology. 24:1406.

Bass, Williamson, Nunan, Humphries, Byron, Morgan, Martin, Humphries. (2011) A syndecan-4 hair trigger initiates wound healing through caveolin- and RhoG-regulated integrin endocytosis. Dev Cell. 21: 681.
http://www.ncbi.nlm.nih.gov/pubmed/21982645

Mahoney, Morgan, Harrison, Humphries, Bass. (2009) Therapeutic ultrasound bypasses canonical syndecan-4 signaling to activate Rac1. J Biol Chem. 284: 8898.

https://www.sheffield.ac.uk/bms/research/bass
"

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