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Structural insights into the pharmacological modulation of cardiovascular ion channels.

PGR-P-174

Key facts

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

Many human diseases result from abnormalities in the function of ion channels, and many successful therapeutic drugs work by activating or blocking ion channels. Our research focuses on understanding the roles in cardiovascular health and disease of tetrameric cation channels formed by the proteins TRPC1, TRPC4 and TRPC5. In order to study specific TRPC1/4/5 channels in cells, tissues and animal models, specific small molecule modulators with known molecular mechanisms of action are required. Despite &gt;15 years of research in the field, the development of such molecules is hindered by the lack of structural insights into TRPC1/4/5 small molecule binding sites, and by the fact that the stoichiometry of biologically relevant TRPC1/4/5 tetramers is not always known.

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

<p>We previously discovered several TRPC1/4/5 modulators, including the xanthine-based small molecule Pico145, a potent TRPC1/4/5 channel inhibitor that shows selectivity for heteromeric TRPC1:C4 channels over other TRPC1/4/5 channels. In this project, we will identify which TRPC1/4/5 tetramers can be formed, how they interact with Pico145, and what the functional outcome of such interactions are.</p> <p>This project may involve cloning and overexpression of different TRPC1/4/5 constructs, photoaffinity labelling of TRPC1/4/5 channels in cells, protein/peptide mass spectrometry, and cryo-electron microscopy of purified proteins.</p> <p>These results will reveal how specific TRPC1/4/5 tetramers can be regulated by small molecules. This will enable future development of small molecules that target specific TRPC4 or TRPC5 channels, which will enable detailed studies of TRPC4/C5 biology and future TRPC4/C5 drug discovery projects.</p> <p><strong>References</strong></p> <p>Minard, A.; Bauer, C.C.; Wright, D.J.; Rubaiy, H.; Muraki, K.; Beech, D.J.; Bon, R.S.&nbsp;<a href="https://www.ncbi.nlm.nih.gov/pubmed/29865154">&lsquo;Remarkable Progress with Small-Molecule Modulation of TRPC1/4/5 Channels: Implications for Understanding the Channels in Health and Disease&rsquo;</a>.&nbsp;<em>Cells</em>&nbsp;<strong>2018</strong>,&nbsp;<em>7</em>, pii: E52.</p> <p><a href="http://blogs.sciencemag.org/pipeline/archives/2017/06/09/the-great-untangling">http://blogs.sciencemag.org/pipeline/archives/2017/06/09/the-great-untangling</a></p> <p>Rubaiy, H.N.; Ludlow, M.J.; Bon, R.S.; Beech, D.J.&nbsp;<a href="https://www.tandfonline.com/doi/full/10.1080/19336950.2017.1317485">&lsquo;Pico145 &ndash; powerful new tool for TRPC1/4/5 channels&rsquo;</a>.&nbsp;<em>Channels</em>&nbsp;<strong>2017</strong>,&nbsp;<em>11</em>, 362-364.</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>