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Understanding the function of the exciting new mechanosensitive channel Piezo1 using molecular simulations, electrophysiology and molecular biology

PGR-P-240

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Key facts

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

Forces that are created by the heart play a vital role in the cardiovascular system as they regulate vascular functions such as endothelial cell alignment to blood flow, red blood cell volume regulation and cardiac remodelling. For this reason, mechanical forces are important in a number of cardiovascular diseases including heart failure and atherosclerosis. Despite some recent advancements, our understanding of how force is sensed at the molecular level by proteins in the cardiovascular system is limited. This project will focus on Piezo1 channel that is a critical mechanical sensor in endothelial cells, red blood cells and other cell types such as cardiac fibroblasts.

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

<p>Piezo1 is a large protein and its function is to permeate ions in response to mechanical stimuli. Mutations on Piezo1 have been shown to result in lymphatic dysplasia in humans, anemias, and potentially other abnormal conditions including heart failure. Whilst a number of recent structural and functional data increased our understanding of Piezo1 function, fundamental aspects of Piezo1 activation and ion transport remain largely unknown partly due to their dynamic nature. Molecular dynamics simulations and molecular modelling are well-established techniques that enable us to follow the dynamics of membrane proteins in a membrane environment. Therefore, they can provide detailed molecular and dynamic understanding of the function of membrane proteins.&nbsp;</p> <p>In this project, the student will use molecular dynamics simulations and molecular modelling to study Piezo1 in model membranes that resemble native membranes in which Piezo1 functions e.g. endothelia membrane and red blood cell membrane. The student will use these simulations to examine the Piezo1 activation and inactivation mechanisms and to investigate the role of different lipid types in regulating Piezo1 function. The student will also use computational methodologies to examine how disease-causing mutations may change Piezo1 activation. The models derived from the computer simulations will be evaluated/refined experimentally, using cell-based assays and molecular biology techniques in Beech/Shi groups.</p> <p>The student will be a part of a multidisciplinary team that already studies Piezo1 and has extensive experience on how to study Piezo1 channel using both advanced computational and lab-based approaches. This position would suit a student with a biology, biochemistry, chemistry or physics background, or a combination of these. Training in molecular simulations or associated computational methods will be provided and therefore no prior experience of computational methods is needed.</p> <h6><br /> References</h6> <p>1.&nbsp;&nbsp; &nbsp;De Vecchis, D., Beech, D.J., and Kalli, A.C.* (2019). Molecular principles of Piezo1 activation by increased membrane tension. BioRxiv 823518. doi:10.1101/823518&nbsp;<br /> 2.&nbsp;&nbsp; &nbsp;Chong, J., De Vecchis, D., Hyman, A.J., Povstyan, O. V, Shi, J., Beech, D.J., and Kalli, A.C.* (2019). Computational reconstruction of the complete Piezo1 structure reveals a unique footprint and specific lipid interactions. BioRxiv 783753. doi:10.1101/783753<br /> 3.&nbsp;&nbsp; &nbsp;Shi J., Hyman A. J., De Vecchis D., Chong J., Lichtenstein L., Futers S. T., Rouahi M, Negre Salvayre A., Auge N, Kalli A.C.* and Beech D. J. 2019. Sphingomyelinase disables Piezo1 channel inactivation to enable sustained response to mechanical force. Cell Reports 33(1), 108225..<br /> 4.&nbsp;&nbsp; &nbsp;Li, J.; Hou, B.; Tumova, S.; Muraki, K.; Bruns, A.; Ludlow, M. J.; Sedo, A.; Hyman, A. J.; McKeown, L.; Young, R. S.; et al. Piezo1 Integration of Vascular Architecture with Physiological Force. Nature 2014, 515 (7526), 279&ndash;282.<br /> &nbsp;</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<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>