Unravelling the mechanisms of action of cardiac myosin modulators in health and heart disease

Cardiac myosin is the molecular motor that drives heart contraction. Direct modulators of cardiac myosin function are promising treatments for inherited heart disease and heart failure. The inherited heart disease hypertrophic cardiomyopathy affects 1 in 500 people and is the most common cause of sudden onset cardiac death in the young, causing approximately 12 deaths in the UK every week. Heart failure is an increasing worldwide public health issue with an estimated prevalence of 64 million people, a mortality rate of approximately 50 % within five years of diagnosis, and an estimated cost to the economy of $346 billion. Current treatments improve heart function but not patient survival. Direct myosin modulators have the potential to do both. Yet, despite a range of pre-clinical studies, we still have very little idea as to how many of these modulators work at the molecular level, which hinders their clinical usage and development.<br /> <br /> This project will investigate the molecular mechanism of action of several modulators in clinical trials for the treatment of inherited heart disease and heart failure. This work builds upon our previous work on the mechanism of action of mavacamten (https://www.biorxiv.org/content/10.1101/2025.02.12.637875v2), a small molecular inhibitor of cardiac myosin that is FDA-approved for the treatment of obstructive hypertrophic cardiomyopathy.  The project will use a combination of molecular and structural biology approaches including molecular cloning, protein expression and purification, cryogenic electron microscopy, structural mass spectrometry and computational modelling to assess the effects of modulator and mutation on cardiac myosin structure and function. Through this approach we will enhance our understanding on the mechanism of action of myosin modulators and provide an experimental pipeline for the structure-guided design of improved myosin modulators with the potential for improved patient outcomes. Full training will be provided on these techniques and you will join a large collaborative and supportive research environment within the Leeds Institute for Cardiovascular & Metabolic Medicine and the Astbury Centre for Structural Molecular Biology. 

<h3><strong>Information about the Award</strong></h3> <p><br /> o    We are offering 1 full-time PHD scholarship in the School of Medicine for one UK candidate, covering a maintenance grant matching UKRI maintenance stipend and UK tuition fees for 3.5 years, subject to satisfactory progress. </p> <h3><br /> <strong>Duration of the Award</strong></h3> <p><br /> o    Full-time (3.5 years). The award will be made for one year in the first instance and renewable for a further period of up to 2.5 years, subject to satisfactory academic progress.</p> <h3><br /> <strong>Other Conditions</strong></h3> <p><br /> o    Applicants must not have already been awarded or be currently studying for a doctoral degree.<br /> o    Awards must be taken up by 1st October 2025.<br /> o    Applicants must live within a reasonable distance of the University of Leeds whilst in receipt of this scholarship.</p> <p> </p>

<p>(if you want to make any changes to the process below please contact your Graduate School admissions team first)</p> <p><br /> To apply for this scholarship opportunity applicants should complete an online application form <a href="https://prod.banner.leeds.ac.uk/ssb/bwskalog_uol.P_DispLoginNon">Admissions Login</a> and attach the following documentation to support their application. </p> <p>o    a full academic CV<br /> o    degree certificate and transcripts of marks<br /> o    Evidence that you meet the University's minimum English language requirements (if applicable)</p> <p>To help us identify that you are applying for this scholarship project please ensure you provide the following information on your application form;</p> <p>o    Select PhD in Medicine as your programme of study<br /> o    Give the full project title and name the supervisors listed in this advert<br /> o    For source of funding please state you are applying for a (Unravelling the mechanisms of action of cardiac myosin modulators in health and heart disease)</p> <p>If English is not your first language, you must provide evidence that you meet the University's minimum English language requirements (below).</p> <p>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. Within the 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. </p>

Applicants to this scholarship in the School of Medicine should normally have an Undergraduate degree of 2:1 or above (or international equivalent) in a relevant subject area. A Master’s degree is desirable, but not essential. Applicants who are uncertain about the requirements for a particular research degree are advised to contact the School or Admissions Team prior to making an application.

The minimum English language entry requirement for postgraduate research study in the School of Medicine 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>The School of Medicine invites applications from prospective postgraduate researchers who wish to commence study for a PhD in the academic year 2025/26. This scholarship is open to UK applicants and covers home fees plus UKRI stipend rates. This fully funded PhD place provides an exciting opportunity to pursue postgraduate research in cardiovascular structural biology.</p>

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