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Role of endothelial mechanosensory protein PIEZO1 in COVID-19 infection and pathogenicity

PGR-P-812

Coronavirus information for applicants and offer holders

We hope that by the time you’re ready to start your studies with us the situation with COVID-19 will have eased. However, please be aware, we will continue to review our courses and other elements of the student experience in response to COVID-19 and we may need to adapt our provision to ensure students remain safe. For the most up-to-date information on COVID-19, regularly visit our website, which we will continue to update as the situation changes www.leeds.ac.uk/covid19faqs

Key facts

Type of research degree
4 year PhD
Application deadline
Ongoing deadline
Country eligibility
International (outside UK)
Funding
Non-funded
Supervisors
Dr Jamel Mankouri and Dr Piruthivi Sukumar
Additional supervisors
Professor David J Beech
Schools
School of Medicine
Research groups/institutes
Leeds Institute of Cardiovascular and Metabolic Medicine
<h2 class="heading hide-accessible">Summary</h2>

Elucidating why the prevalence and severity of COVID-19 vary across ethnic groups is essential to identify vulnerable populations and find drug targets by understanding the pathogenesis. SARS-CoV-2 viral particles enter the human cells through the plasma membrane by binding/interacting with membrane proteins. Upon analysing the genomic data of COVID-19 patients, we found specific single nucleotide polymorphisms (SNPs) in PIEZO1, a gene encoding the remarkable mechanosensing membrane protein PIEZO11. Prevalence of those SNPs varied across ethnic groups. By forming mechanosensitive cation-permeable channels, PIEZO1 controls membrane structure and function in vascular and blood cells such as endothelial cells (EC), platelets and immune cells. In particular, PIEZO1 regulates angiogenesis, vascular permeability, inflammation and maintains an anti-thrombotic milieu in blood and vascular wall2. Notably, SARS-CoV-2-induced respiratory insufficiency is triggered by inflammation, excessive pulmonary vascular angiogenesis and permeability, and diffuse thromboembolic events3. Moreover, SARS-CoV-2 can directly infect EC. Hence, we propose to investigate whether the SNPs we found in PIEZO1 of COVID-19 patients modulate PIEZO1 function in EC and alter the susceptibility to severe COVID-19.

<h2 class="heading hide-accessible">Full description</h2>

<p>The research fellow will use cellular over-expression system and human EC with specific mutations to study the effect of SNPs on PIEZO1 activity and functions relevant to COVID-19 pathophysiology. SARS-CoV-2 live virus along with pharmacological PIEZO1 modulators will be used to elucidate the role of PIEZO1 in viral entry and pathogenesis in EC. The fellow will be trained in cell/molecular biology, endothelial and ion channel pathophysiology, basic virology and animal models of disease and work as a part of a vibrant multidisciplinary research team. The fellow will have full access to our state-of-the-art biomedical research facilities, pre-clinical imaging suite and animal unit. Aim of the project is to acquire specific knowledge on the role of PIEZO1 on SARS-CoV-2 viral entry and pathogenesis and also the vascular effects of COVID-19 which will allow for rapid translation of the laboratory results towards clinical application.</p> <h6>References</h6> <p>1. Cheng, C. W. et al. <a href="http://medrxiv.org/lookup/doi/10.1101/2020.06.01.20119651">Ethnically diverse mutations in PIEZO1 associate with SARS-CoV-2 positivity</a>&nbsp;(2020) doi:10.1101/2020.06.01.20119651.<br /> 2. Beech, D. J. &amp; Kalli, A. C. Force Sensing by Piezo Channels in Cardiovascular Health and Disease. Arterioscler. Thromb. Vasc. Biol. 39, 2228&ndash;2239 (2019).<br /> 3. Kang, Y. et al. Cardiovascular manifestations and treatment considerations in covid-19. Heart heartjnl-2020-317056 (2020) doi:10.1136/heartjnl-2020-317056.</p>

<h2 class="heading">How to apply</h2>

<p>Please note these are not standalone projects and applicants must apply to the PhD academy directly.</p> <p>Applications can be made at any time. To apply for this project applicants should complete a&nbsp;<a href="https://medicinehealth.leeds.ac.uk/downloads/download/129/faculty_graduate_school_-_application_form">Faculty Application Form</a> and send this alongside a full academic CV, degree transcripts (or marks so far if still studying) and degree certificates to the Faculty Graduate School <a href="mailto:fmhpgradmissions@leeds.ac.uk">fmhpgradmissions@leeds.ac.uk</a></p> <p>We also require 2 academic references to support your application. Please ask your referees to send these <a href="https://medicinehealth.leeds.ac.uk/downloads/download/130/faculty_graduate_school_-_scholarship_reference_form">references</a> on your behalf, directly to <a href="mailto:fmhpgradmissions@leeds.ac.uk">fmhpgradmissions@leeds.ac.uk</a></p> <p>If you have already applied for other projects using the Faculty Application Form this academic session you do not need to complete this form again. Instead you should email fmhgrad to inform us you would like to be considered for this project.</p> <p>If English is not your first language, you must provide evidence that you meet the University&#39;s minimum English language requirements (below).</p>

<h2 class="heading heading--sm">Entry requirements</h2>

A degree in biological sciences, dentistry, medicine, midwifery, nursing, psychology or a good honours degree in a subject relevant to the research topic. A Masters degree in a relevant subject may also be required in some areas of the Faculty. For entry requirements for all other research degrees we offer, please contact us.

<h2 class="heading heading--sm">English language requirements</h2>

Applicants whose first language is not English must provide evidence that their English language is sufficient to meet the specific demands of their study. The Faculty of Medicine and Health minimum requirements in IELTS and TOEFL tests for PhD, MSc, MPhil, MD are: &acirc;&euro;&cent; British Council IELTS - score of 7.0 overall, with no element less than 6.5 &acirc;&euro;&cent; TOEFL iBT - overall score of 100 with the listening and reading element no less than 22, writing element no less than 23 and the speaking element no less than 24.

<h2 class="heading">Contact details</h2>

<p>For further information please contact the Graduate School Office<br /> e:<a href="mailto:fmhpgradmissions@leeds.ac.uk">fmhpgradmissions@leeds.ac.uk</a></p>


<h3 class="heading heading--sm">Linked research areas</h3>