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MRC DiMeN Doctoral Training Partnership: Mechanical activation of TGFbeta signaling in arterial disease

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  • Full or part time
    Prof P Evans
    Prof Helen Arthur
  • Application Deadline
    No more applications being accepted
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

Atherosclerosis, a disease of arteries that leads to angina, heart attack and stroke, develops at branches and bends of arteries that are exposed to disturbed patterns of blood flow. The primary supervisor recently demonstrated that endothelial cells at disease-prone sites undergo a process called endothelial-to-mesenchymal transition (EndMT). This is characterised by multiple morphological and physiological changes including loss of cell polarity, disruption of intercellular junctions, increased proliferation, and migration of cells into surrounding tissue. Aside from its well described role in development, recent studies implicated EndMT in the pathophysiology of atherosclerosis. The proposed PhD studentship will determine the signalling pathways responsible for inducing EndMT in atherosclerosis focussing on the roles of TGF BMPs, and SMAD transcription factors which are known to drive EndMT in other systems e.g. cancer.

HYPOTHESIS. We hypothesize that disturbed flow induces EndMT via the activation of specific TGFand BMPs pathways thereby promoting atherosclerosis initiation.

EXPERIMENTAL PLAN.
YEAR 1. In vitro studies. The student will determine whether TGF BMP2, BMP4, their receptors (ALK1/5/2/3/6, Type II TGF receptor (Tgfbr2), endoglin) and SMADs are essential for EndMT using human coronary artery EC (HCAEC) exposed to flow (primary supervisor has expertise and equipment for flow responses).

YEAR 2. Correlating TBG/BMP signalling with early atherogenesis. The expression of TGF BMP2, BMP4, their receptors and SMADs will be quantified in diseased arteries of hypercholesterolaemic ApoE-/- mice (exposed to a high fat diet for 6 weeks) by en face staining.

YEAR 3. Genetic deletion studies in mice will be performed to establish a causal link between TGF or BMP signalling and EndMT at atheroprone sites. State-of-the art conditional knockout strategies will be used to delete receptors in these pathways (endoglin, ALK1 and Tgfbr2) from endothelial cells (by crossing mutant ‘floxed’ strains with mice carrying inducible endothelial-specific Cdh5CreERT2). The effect of deleting specific receptors will be assessed by quantifying EndMT and disease markers in arteries.

VALUE. Our proposed studies will elucidate the ‘wiring’ of upstream mechanosensitive signalling components that regulate EndMT expression at atheroprone regions. They have translational value because they may identify molecules that can be targeted therapeutically to reduce atherosclerosis and thereby help to prevent angina, heart attack and stroke.

Benefits of being in the DiMeN DTP:
This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.
We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.
Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards
Further information on the programme can be found on our website:
http://www.dimen.org.uk/

Funding Notes

Studentships are fully funded by the Medical Research Council (MRC) for 3.5yrs
Includes:
Stipend at national UKRI standard rate
Tuition fees
Research training and support grant (RTSG)
Travel allowance
Studentships commence: 1st October 2019.

To qualify, you must be a UK or EU citizen who has been resident in the UK/EU for 3 years prior to commencement. Applicants must have obtained, or be about to obtain, at least a 2.1 honours degree (or equivalent) in a relevant subject. All applications are scored blindly based on merit. Please read additional guidance here: https://goo.gl/8YfJf8
Good luck.

References

Feng S, Bowden N, Fragiadaki M, Souilhol S, Hsaio S, Mahmoud M, Allen S, Pirri D, Tardajos Ayllon B, Akhtar S, Thompson AAR, Jo H, Weber C, Ridger V, Schober A, Evans PC. (2017) Mechanical activation of HIF1 drives endothelial dysfunction at atheroprone sites. Arterioscler Thromb Vasc Biol. 37;2087-2101.

Mahmoud M, Kim HR, Xing R, Hsiao S, Mammmoto A, Chen J, Serbanovic-Canic J, Feng S, Bowden NP, Maguire R, Ariaans M, Francis S, Weinberg PD, Van der Heiden K, Jones EA, Chico TJ, Ridger VC, Evans PC. (2016) TWIST1 Integrates Endothelial Responses to Flow in Vascular Dysfunction and Atherosclerosis. Circ Res. 119: 450-462.

Kwak BR, Back M, Bochaton-Piallat M-L, Caligiuri G, Daemen MJAP, Davies PF, Hoefer IE, Holvoet P, Jo H, Krams R, Lehoux S, Monaco C, Steffens S, Virmani R, Weber C, Wentzel JJ, Evans PC. (2014) Biomechanical factors in atherosclerosis: mechanisms and clinical implications. Eur Heart J 35(43):3013-3020.



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