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Computational approaches to understanding the mechanosensitive Piezo1 channel activation mechanism.

PGR-P-240

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
Schools
School of Medicine
Research groups/institutes
Leeds Institute of Cardiovascular and Metabolic Medicine
<h2 class="heading hide-accessible">Summary</h2>

Mechanical forces play a very important role in the cardiovascular system as they regulate vascular functions such as endothelial cell alignment to blood flow, endothelium-dependent vasodilation and cardiac remodeling. For this reason, mechanical forces are important in a number of cardiovascular diseases. 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 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. Three recent electron microscopy (EM) structures showed that Piezo1 exists in a trimeric form in the membrane.</p> <p>The three Piezo1 subunits form a pore region with a C-terminal extracellular domain between the last two transmembrane helices. 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 party due to their dynamic nature. Molecular dynamics simulations are a well-established technique that enables us to follow the dynamics of membrane proteins in a membrane environment.</p> <p>Therefore, it can provide detailed molecular and dynamic understanding of the function of membrane proteins. In this project, the student will use molecular dynamics simulations and molecular modelling to simulate Piezo1 in model membranes that resemble native membranes in which Piezo1 functions e.g. endothelia membrane and red blood cell membrane.</p> <p>The student will use these simulations to examine the Piezo1 activation and inactivation mechanisms and to investigate the role of the membrane environment in regulating Piezo1 function. The student will also use computational methodologies that were developed in the Kalli group 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 project will suit anyone wishing to learn a range of complementary skills, including both computational and lab-based skills.</p> <h3>References:</h3> <p>Kalli, A. C.; Reithmeier, R. A. F. Interaction of the Human Erythrocyte Band 3 Anion Exchanger 1 (AE1, SLC4A1) with Lipids and Glycophorin A: Molecular Organization of the Wright (Wr) Blood Group Antigen. PLoS Comput. Biol. 2018, 14 (7), e1006284.</p> <p>Kalli, A. C.; Sansom, M. S. P.; Reithmeier, R. A. F. Molecular Dynamics Simulations of the Bacterial UraA H+-Uracil Symporter in Lipid Bilayers Reveal a Closed State and a Selective Interaction with Cardiolipin. PLoS Comput. Biol. 2015, 11 (3), e1004123.</p> <p>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.</p> <p>Li, J.; Hou, B.; Beech, D. J. Endothelial Piezo1: Life Depends on It. Channels 2015, 9 (1), 1&ndash;2.</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>, t: +44 (0)113 343 8221</p>


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