Basis: Full Time Closing Date: 23.59 hours BST on Sunday 30 April 2023 Reference: R230069 Release Date: Tuesday 14 March 2023
Supervisor: Dr Jill Johnson
Project Reference: HLSJohnsonFibrosis
Key words: fibrosis, pericyte, regenerative medicine, cell culture, differentiation, mouse model
Applications are invited for a four-year Postgraduate studentship, as part of the MIBTP programme, to be undertaken within the Biosciences Research Group at Aston University. The successful applicant will join an established experimental group working on the mechanisms driving tissue fibrosis. The studentship is offered in collaboration with the company Stemcell Technologies.
The position is available to start in October 2023.
This studentship includes a fee bursary to cover the home fees rate, plus a maintenance allowance (£17,668 p.a. in 2022/3).
Overseas applicants may apply for this studentship but will need to pay the difference between the ‘Home' and the ‘Overseas' tuition fees. Currently the difference between ‘Home' and the ‘Overseas' tuition fees is £10,504 in 2022/3. As part of the application, you will be required to confirm that you have applied for or secured this additional funding.
Background to the Project
Scar formation is a vital mechanism of tissue repair following injury. However, healthy tissue repair can develop into pathological fibrosis, which ultimately leads 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 significant 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 will build on previous work in Dr Jill Johnson's research group that has identified pericytes as the primary driver of fibrosis. Pericytes are a type of mesenchymal progenitor cell that support capillaries throughout the body1 and are particularly important in maintaining healthy tissue structure. Importantly, 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 myofibroblasts5,6 (Figure 1). However, the mechanism by which chronic inflammation affects the differentiation capacity of pericytes is currently unknown.
Mesenchymal stem cells (MSCs) are multipotent adult stem cells with self- renewal and differentiation capacity that can be readily isolated from bone marrow, but all tissues harbor MSC-like cells as part of the microvasculature, i.e. pericytes. MSCs can differentiate into multiple cell lineages under specific differentiation conditions. Intriguingly, recent studies have shown that inflammatory mediators affect the differentiation capacity of MSCs, i.e. low levels of TNF-α promote osteogenic differentiation in bone marrow-derived MSCs.7
Aims: To investigate the mechanisms regulating the differentiation capacity of pericytes in health and disease.
Hypothesis: Pro-fibrotic growth factors will lead to pericyte- myofibroblast transition and contribute to fibrosis.
1. Using in vitro two-dimensional pericyte culture, we will investigate the mechanisms of pericyte-to-myofibroblast differentiation.
2. Differentiation assays will be performed on healthy and inflammatory- mediator treated human pericytes. Readouts will include qPCR array analysis (Human Mesenchymal Stem Cell qPCR Array, Stemcell Technologies) and MSC differentiation assays to assess the capacity of pericytes to differentiate into adipocytes, chondrocytes, and osteocytes using MesenCult™ differentiation kits (Stemcell Technologies).
3. Experiments will be performed to validate the findings from the first two aims in an in vivo setting.
Expected outcomes. Pericytes will respond to inflammatory mediators by transforming into myofibroblasts and demonstrating more robust differentiation capacity.
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. Bignold R et al. (2021) Front Allergy 2:786034. 6. Bignold R et al. (2022) Respir Res. 2022 23(1):183. 7. Russell T et al. (2021) Cells 10(2):341. 8. Johnson JR (2004) Am J Respir Crit Care Med 169(3):378-85.
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 Biochemistry, Biological Sciences or related subject. Preferred skill requirements include knowledge/experience of mammalian cell culture and mesenchymal stem cell differentiation assays. Previous experience working with mice is preferred but not essential.
Candidates are encouraged to contact Dr Jill Johnson to discuss the project before applying if they wish to.
Contact: Dr Jill Johnson , Aston University
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