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Interrogating the cellular and molecular mechanisms of tissue fibrosis - Reference: MIBTP_Johnson_Fibrosis


   College of Health and Life Sciences

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  Dr J Johnson  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

Birmingham United Kingdom Immunology Structural Biology

About the Project

Applications are invited for four year Postgraduate studentships, supported by the Midlands Integrative Biosciences Training Partnership (MIBTP) (URL: https://warwick.ac.uk/fac/cross_fac/mibtp/pgstudy/phd_opportunities/structural_biology/activation) and Biotechnology and Biological Sciences Research Council (BBSRC) (URL: https://bbsrc.ukri.org/). Up to 2 studentships are available.

The studentships are available to start in October 2021.

Background to the Studentship

MIBTP scholars join a programme of skills training in year 1. Applicants are required to select an area of study (URL: https://warwick.ac.uk/fac/cross_fac/mibtp/areas_of_research/), but may join the programme with or without selecting a preferred project. The skills training programme includes short rotation projects and students are able to choose a PhD project once they have experienced these differing research environments.

Potential PhD projects are provided to give applicants an idea of the breadth of research within MIBTP and specific research topics at Aston University. You can browse the other projects available here (URL: https://www.findaphd.com/phds/program/midlands-integrative-biosciences-training-partnership-mibtp-funded-phd-studentships/?i369p1045). Additional projects will become available during Year 1 and students can work with potential supervisors during their first year to develop a particular project.

Project Outline

Scar formation is a vital mechanism of tissue repair following injury. However, healthy tissue repair can develop into pathological fibrosis, leading to tissue destruction and organ failure. Fibrosis is associated with chronic inflammation, oxidative stress, and ageing. However, there are currently no treatment options for organ fibrosis, and these diseases impose a burden on public health care systems and have detrimental impacts on patient quality of life. Importantly, little is known about the factors that initiate fibrosis. This studentship builds on the research group’s previous work that has identified pericytes as the primary driver of fibrosis. Pericytes provide support to capillaries throughout the body1 and are important in maintaining healthy tissue structure. Pericytes are strongly associated with tissue fibrosis in the lung, liver, and kidney.2-4 Recent studies have shown that pericytes contribute to fibrosis by uncoupling from local blood vessels, followed by migration to the site of inflammation and differentiation into scar-forming myofibroblasts5 (Figure 1). However, the mechanisms by which pericytes transform into scar-forming cells (myofibroblasts) are currently unknown.

The mechanical microenvironment of cells has a significant effect on their activity and proliferation, driving the progression of fibrosis.6 The stiffness (Young’s elastic modulus) of human tissue ranges from 0.1-10 kPa,7 which significantly deviates from traditional plastic culture platforms (Young’s elastic modulus in the order of GPa). This study will mimic the mechanical microenvironment of healthy and fibrotic tissue using innovative cell culture techniques.

Aims: To investigate the mechanisms responsible for myofibroblast transformation. using in vitro methods to assess the impact of fibrotic mediators on pericyte function.

Hypothesis: Pro-fibrotic growth factors will lead to pericyte-myofibroblast transition and contribute to fibrosis.

Methods: 1. Using in vitro two-dimensional pericyte culture, we will determine the dose and duration of fibrosis-associated growth factor treatment (EGF, bFGF, and TGF-β) resulting in pericyte transition into myofibroblasts. The readouts will include procollagen I and α-smooth muscle actin expression, cell migration using scratch assays, and cell contractility using collagen gel contraction assays.

2. Establish microvascular organoids using the n3D NanoShuttle-PL magenetic system. These organoids are composed of human pericytes and endothelial cells to mimic the microvascular environment and to establish the impact of growth factor treatment on pericyte/endothelial cell connectivity and vascular stability. Readouts will include the analysis of confocal images of immunostained organoids following dose-response and time-response studies.

3. Mimic the mechanical microenvironment of healthy and fibrotic tissue using chemically tailored hydrogels that incorporate biocompatible materials such as collagen, agarose, or gellan gum via mechanical methods or chemical crosslinking. By modifying the chemical composition, gelling temperature, and stirring speeds, stiffness (Young’s elastic modulus) values that are representative of human tissue can be achieved (from hundreds of Pascals (Pa) to tens of kPa), as opposed to traditional plastic culture platforms (on the order of GPa).

Expected outcomes. The induction of fibrosis in pericytes will lead to:

• increased expression of procollagen I and α-smooth muscle actin, known to be associated with fibrosis

• decreased microvascular organoid stability

• increased expression of pro-fibrotic markers by pericytes grown in a stiff matrix

It is expected that these outcomes will contribute to describing the molecular mechanisms by which pericytes initiate fibrosis.

Person Specification

The successful applicant should have been awarded, or expect to achieve, a Masters degree in a relevant subject with a 60% or higher weighted average, and/or a First or Upper Second Class Honours degree (or an equivalent qualification from an overseas institution) in a relevant subject. Full entry requirements for Aston University can be found on our website (URL: https://www.aston.ac.uk/study/courses/phd-life-and-health-sciences).

Full entry requirements for MIBTP can be found on their website (URL: https://www.aston.ac.uk/study/courses/phd-life-and-health-sciences).

Contact information

For further information on the advertised project, contact Dr Jill Johnson [Email Address Removed]

Submitting an application

Details of how to apply for the studentship can be found here (URL: https://jobs.aston.ac.uk/Vacancy.aspx?ref=R210130).

If you require further information about the application process contact the Postgraduate Admissions team [Email Address Removed]


Funding Notes

The studentships include a fee bursary to cover the Home fees rate, plus a tax free stipend of at least £15,285 p.a (to rise in line with UKRI recommendation).

Overseas Applicants
Overseas applicants may apply, and the home fees rate will be covered. Funding will not cover the difference between UK tuition fees and international tuition fees (currently £13,443 in 2020/21); international tuition fee payers will be required to fund the fee difference themselves. MIBTP encourages international students with existing sources of funding (e.g. fellowships) to apply. Please confirm in your application how you will fund the fee difference.

References

1. Fuxe J et al. (2011) Am J Pathol 178:2897 2. Johnson JR et al. (2015) Am J Physiol Lung Cell Mol Physiol 308(7):L658 3. Mederacke I et al. (2013) Nat Commun 4:2823 4. Wu CF et al. (2013) Am J Pathol 182:118 5. Hosaka K et al. (2016) Proc Natl Acad Sci USA 113:E5618 6. Wells et al. (2013) Biochim Biophys Acta 1832:884. 7. Achterberg et al. (2014) J Invest Dermatol 134:1862.