LICAMM Molecular characterization and functional roles of volume-regulated ion channels in platelets

Blood platelets play a pivotal role in the development of atherosclerosis and their dysfunction would lead to a number of cardiovascular diseases. Mean platelet volume, reflecting the average size of platelets in circulation, correlated with platelet function and could be used as a biomarker in a variety of disorders and a surrogate marker of platelet activation.

<p>The regulation of cell volume requires appropriate and timely changes of intracellular concentrations of ions or organic osmolytes in cells. Volume-regulated anion channels (VRACs) have been shown to contribute to the process of cell volume change. Quite recently, LRRC8A, leucine-rich repeat-containing protein 8A (also known as SWELL1), has been recognized as an essential component for VRAC in many cell types. Its paralogues LRRC8B, LRRC8C, LRRC8D, or LRRC8E have also be suggested to form VRACs with the obligatory LRRC8A, depending on cell types.</p> <p>Although volume regulation is one of the key features for blood platelets, the molecular identity of volume-regulated ion channels in platelets and their relevance to major functions of platelets are completely unknown.</p> <p>In this project the student will combine state-of-the-art high-definition electrophysiological recordings in native platelets with functional assays to reveal the molecular identity of volume-regulated ion channels in platelets and how these ion channels are involved in the activation and reactivity of platelets. The specific objectives include:</p> <ol> <li>To determine the molecular identity of volume-regulated ion channels in native platelets through high-definition electrophysiological recordings which will be further complemented by molecular biology and biochemical methods;</li> <li>To determine how the identified channels are involved in the activation and aggregation of platelets through pharmacological and genetic manipulation approaches;</li> <li>To determine the cellular mechanism underlying the effects of the ion channels on platelet functions through pharmacological and protein-omics approaches.</li> </ol> <p>The student will learn cutting-edge electrophysiological recordings in native cells with different configurations, platelet function assays, molecular biology and biochemical method which are already well-established at Leeds. The student will be based in the Leeds Institute of Cardiovascular and Metabolic Medicine which is already reputed for conducting high-impact research that has real-world impact, improving peoples' lives and addressing the world's healthcare challenges. The existing cross-disciplinary approaches will allow the student to receive extensive trainings on all methods necessary for cardiovascular research. This opportunity would suit a student with the background of medicine, biology, biochemistry, or a combination of these. No prior research experience is required.</p> <h5>References</h5> <ol> <li>Aburima A, Berger M, Spurgeon BEJ, Webb BA, Wraith KS, Febbraio M, Poole AW, Naseem KM. <a href="https://pubmed.ncbi.nlm.nih.gov/33538796/">Thrombospondin-1 promotes hemostasis through modulation of cAMP signaling in blood platelets.</a> Blood. 2021,137:678-689.</li> <li>Hindle MS, Spurgeon BEJ, Cheah LT, Webb BA, Naseem KM. Multidimensional flow cytometry reveals novel platelet subpopulations in response to prostacyclin. J Thromb Haemost. 2021, 19:1800-1812. <a name="baep-author-id1"></a></li> <li><a href="https://www.sciencedirect.com/science/article/pii/S0268960X05800207#!">Jackson SR</a><a name="baep-author-id2"></a>, Carter JM. Platelet volume: Laboratory measurement and clinical application. <a href="https://www.sciencedirect.com/journal/blood-reviews" title="Go to Blood Reviews on ScienceDirect">Blood Reviews</a>. 1993, 7:104-113</li> <li>Schmoeller D, Picarelli MM, Paz Munhoz T, Poli de Figueiredo CE, Staub HL. Mean Platelet Volume and Immature Platelet Fraction in Autoimmune Disorders. Front Med (Lausanne). 2017, 4:146.</li> <li>Voss FK, Ullrich F, Münch J, Lazarow K, Lutter D, Mah N, Andrade-Navarro MA, von Kries JP, Stauber T, Jentsch TJ. Identification of LRRC8 heteromers as an essential component of the volume-regulated anion channel VRAC. Science. 2014, 344:634-8.</li> <li>Qiu Z, Dubin AE, Mathur J, Tu B, Reddy K, Miraglia LJ, Reinhardt J, Orth AP, Patapoutian A. SWELL1, a plasma membrane protein, is an essential component of volume-regulated anion channel. Cell. 2014, 157:447-458.</li> <li>Syeda R, Qiu Z, Dubin AE, Murthy SE, Florendo MN, Mason DE, Mathur J, Cahalan SM, Peters EC, Montal M, Patapoutian A. LRRC8 Proteins Form Volume-Regulated Anion Channels that Sense Ionic Strength. Cell. 2016, 164:499-511. </li> <li>Shi J, Miralles F, Birnbaumer L, Large WA, Albert AP. Store-operated interactions between plasmalemmal STIM1 and TRPC1 proteins stimulate PLCβ1 to induce TRPC1 channel activation in vascular smooth muscle cells. J Physiol. 2017, 595:1039-1058. </li> <li>Shi J, Hyman AJ, De Vecchis D, Chong J, Lichtenstein L, Futers TS, Rouahi M, Salvayre AN, Auge N, Kalli AC, Beech DJ. 2020. Sphingomyelinase Disables Inactivation in Endogenous PIEZO1 Channels. Cell Rep.</li> <li>Rode B, Shi J, Endesh N, Drinkhill MJ, Webster PJ, Lotteau SJ, Bailey MA, Yuldasheva NY, Ludlow MJ, Cubbon RM, Li J, Futers TS, Morley L, Gaunt HJ, Marszalek K, Viswambharan H, Cuthbertson K, Baxter PD, Foster R, Sukumar P, Weightman A, Calaghan SC, Wheatcroft SB, Kearney MT, Beech DJ.  2017. Piezo1 channels sense whole body physical activity to reset cardiovascular homeostasis and enhance performance.  Nat Commun. 8(1):350. </li> </ol> <p> </p>

<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>

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 areas is desirable but not essential.

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 minimum requirements for this programme in IELTS and TOEFL tests are: • British Council IELTS - score of 7.0 overall, with no element less than 6.5 • 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.

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