LICAMM Understanding how cells sense mechanical forces in health and disease

From the flow of blood through our arteries to the development and ageing of tissues, mechanical forces influence virtually every aspect of biology. Understanding how cells detect and respond to these forces is an unresolved but exciting challenge in biomedical sciences. This PhD project offers an opportunity to uncover the molecular mechanisms that enable cells to sense mechanical force. The student will investigate PIEZO1, a mechanosensitive ion channel that acts as a key force sensor in cardiovascular and many other systems, including the immune, nervous, reproductive and respiratory systems. Malfunction of PIEZO1 has been implicated in human 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 PIEZO1 are important. Therefore, investigating the mechanisms by which PIEZO1 channels sense and respond to mechanical forces is critical as it can lead to molecular understanding of cardiovascular and other diseases.

<p>Recent work from our team uncovered a novel mechanism that regulates PIEZO1 force sensing. This mechanism involves interactions between neighbouring channel subunits and is strongly influenced by the surrounding membrane lipids. However, the molecular basis of this lipid-dependent regulation remains poorly understood. </p> <p>In this study, the student will combine state-of-the-art molecular dynamics simulations with experimental approaches, including electrophysiology and molecular biology, to uncover how the lipid environment shapes PIEZO1 structure, function, and force sensitivity. Molecular dynamics simulations are a well-established technique that enables us to follow the dynamics of membrane proteins in a membrane environment. This project will provide unprecedented molecular insight into how cell membrane composition regulates mechanosensitive ion channels. Understanding these mechanisms will advance our knowledge of fundamental biological processes while informing future structure-based drug discovery for PIEZO1-related disorders. </p> <p>The successful candidate will join a highly collaborative and multidisciplinary research team that already studies PIEZO1 channels and has extensive experience of using advanced computational and lab-based approaches to study these channels. They will receive training in advanced computational and laboratory techniques and contribute to cutting-edge research at the interface of biology, physics, and medicine.</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>