LICAMM Computer simulations of PIEZO force detection in cardiovascular disease

Mechanical forces are required for many functions in biology e.g., 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 several cardiovascular diseases including heart failure, hypertension, and atherosclerosis. However, how force is sensed in cardiovascular health and disease is currently an important but unresolved question in biology. This project will use state-of-the-art computational methodologies to answer this question. This new knowledge is critical, and it will enable new and improved therapeutic approaches for cardiovascular diseases. <br /> <br /> The PIEZO mechanosensitive ion channels were identified as key sensors of mechanical forces in cardiovascular health and disease. The PIEZO family has two members: PIEZO1 and PIEZO2. They are critical mechanical sensors in endothelial cells, red blood cells, cardiac fibroblasts, cardiac nerves and other cell types. Both proteins form large ion channels, and their function is to permeate ions in response to mechanical stimuli. Malfunction of PIEZOs has been implicated in a number of human cardiovascular diseases including dehydrated hereditary stomatocytosis, lymphatic dysplasia, varicose vein disease, pulmonary hypertension, heart failure and cardiotoxicity caused by chemotherapy. In some cases, genetic variations in the PIEZOs are important. Therefore, investigating the mechanisms by which PIEZO and PIEZO variant channels are able to sense and respond to mechanical forces is critical as it can lead to molecular understanding of cardiovascular and other diseases.

<p>In this project the student will use molecular dynamics simulations and molecular modelling to determine how the membrane environment regulates the function of PIEZO channels. Molecular dynamics simulations are a well-established technique that enables 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. The specific Objective are: </p> <ol> <li>Build computer models of human PIEZO and PIEZO variant channel activation by membrane stretch and fluid flow.</li> <li>Determine how lipids in the membrane regulate PIEZO dynamics and responses to forces.</li> </ol> <p>This project will enable the student to develop cutting-edge computational skills that may dramatically improve the possibility to predict disease outcomes based on genetic data. The student will be a part of a multidisciplinary team that already studies PIEZO channels and has extensive experience on how to investigate them using both advanced computational and lab-based approaches. This opportunity 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 is needed.</p> <h5>References</h5> <ol> <li>Beech, D.J., A.C. Kalli, B.D. J., and K.A. C. 2019. Force Sensing by Piezo Channels in Cardiovascular Health and Disease. Arterioscler. Thromb. Vasc. Biol. 39:2228–2239, doi: 10.1161/ATVBAHA.119.313348.</li> <li>Smith, K.A., E. Chuntharpursat-Bon, O. V Povstyan, M. Debant, J.A. Kinsella, C. Revill, C. Fagnen, J. Shi, R. Foster, D.J. Beech, and A.C. Kalli. 2025. Regulation of PIEZO1 channel force sensitivity by interblade handshaking. Sci. Adv. 11:eadt7046, doi: 10.1126/sciadv.adt7046.</li> <li>De Vecchis, D., D.J. Beech, and A.C. Kalli. 2021. Molecular dynamics simulations of Piezo1 channel opening by increases in membrane tension. Biophys. J. 120:1510–1521, doi: 10.1016/j.bpj.2021.02.006.</li> <li>Chong, J., D. De Vecchis, A.J. Hyman, O. V Povstyan, M.J. Ludlow, J. Shi, D.J. Beech, and A.C. Kalli. 2021. Modeling of full-length Piezo1 suggests importance of the proximal N-terminus for dome structure. Biophys. J. 120:1343–1356, doi: 10.1016/j.bpj.2021.02.003.</li> <li>Beech, D.J., C. Fagnen, and A.C. Kalli. 2024. Biological sensing of fluid flow—lessons from PIEZO1. Biophys. Rev. 16:871–873, doi: 10.1007/s12551-024-01246-x.</li> </ol>

<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. You should complete an <a href="https://medicinehealth.leeds.ac.uk/faculty-graduate-school/doc/apply-2">online application form</a> and attach the following documentation to support your application. </p> <ul> <li>a full academic CV</li> <li>degree certificate and transcripts of marks (or marks so far if still studying)</li> <li>Evidence that you meet the programme’s minimum English language requirements (if applicable, see requirement below)</li> <li>Evidence of funding to support your studies</li> </ul> <p>To help us identify that you are applying for this project please ensure you provide the following information on your application form;</p> <ul> <li>Select PhD in Medicine, Health & Human Disease as your planned programme of study</li> <li>Give the full project title and name the supervisors listed in this advert</li> </ul> <p><em>As an international research-intensive university, we welcome students from all walks of life and from across the world. We foster an inclusive environment where all can flourish and prosper, and we are proud of our strong commitment to student education. Across all Faculties we are dedicated to diversifying our community and we welcome the unique contributions that individuals can bring, and particularly encourage applications from, but not limited to Black, Asian, people who belong to a minority ethnic community, people who identify as LGBT+ and people with disabilities. Applicants will always be selected based on merit and ability.</em></p>

Applicants to research degree programmes should normally have at least a first class or an upper second class British Bachelors Honours degree (or equivalent) in an appropriate discipline. The criteria for entry for some research degrees may be higher, for example, several faculties, also require a Masters degree.

If English is not your first language, you must provide evidence that you meet the University's minimum English language requirements. The minimum English language entry requirement for postgraduate research study in the School of Medicine for 2027/28 is an IELTS of 6.5 overall with at least 6.0 in each component (reading, writing, listening and speaking) or equivalent. The test must be dated within two years of the start date of the course in order to be valid.

<p>This project is open to applicants who have the funding to support their own studies or who have a sponsor who will cover these costs.</p>

<p>For further information about the admissions process please contact the Faculty Admissions Team:<br /> e:<a href="mailto:hlspgradmissions@leeds.ac.uk">hlspgradmissions@leeds.ac.uk</a></p>