LICAMM The role of dietary compounds in modulation of thrombo-inflammatory risk in diabetes

Risk of thromboinflammation, referring to the coordinated activation of thrombotic and inflammatory processes, is increased in patients with diabetes and other metabolic disorders. Obesity is a major risk factor for diabetes and approximately two thirds of adults in the UK are overweight or obese.

<p class="paragraph" style="text-align: justify;">Chronic inflammation has been implicated as one of the main mechanisms contributing to the development of thrombosis in obese patients, highlighting the need for novel targets for therapeutics to treat and prevent thrombosis in patients with a heighten inflammatory state. Platelets and fibrin play a crucial role in haemostasis and thrombosis, while neutrophils, the most abundant leucocyte, are central to the innate immune response against microbial infection. Neutrophils may release extracellular traps (NETs) via a processed termed NETosis when activated in response to microbial infection and thrombosis development, where NETs themselves have shown the ability to induce clotting. The interaction of neutrophils with platelets has been implicated in the development of thromboinflammation but further research is required to determine potential mechanisms to attenuate this interaction. We have shown that the interaction of fibrin with platelet receptor GPVI contributes to procoagulant platelet formation in vitro and that inhibiting GPVI signalling alters blood clot characteristics that are associated with a pro-thrombotic clot phenotype. Further investigations are required to determine whether changes in clot structure can substantially decrease thromboinflammation in patients with diabetes.</p> <p class="paragraph" style="text-align:justify">It is well-established that dietary habits have an impact on diabetes, obesity and cardiovascular disease risk. Post-prandial glycaemic responses have been shown to be modulated by certain polyphenols, which are compounds derived from plants. Polyphenols have also been shown to decrease platelet-neutrophil aggregation and oxidative stress in hyperglycaemia, however, further research is required to determine the long-term effect of polyphenols on thromboinflammation.</p> <h5>Project aims</h5> <p>This project will investigate the effect of polyphenols from different classes (phenolic acids, flavonoids, stilbenes and lignans) on platelet-neutrophil aggregation, platelet mitochondria number and platelet procoagulant activity. Furthermore, this project will determine the effect of polyphenols on the characteristics of clot structure commonly associated with a pro-thrombotic phenotype.</p> <h5>Plan of investigation</h5> <p>The student will screen a number of polyphenolic compounds for their acute effect on platelet-neutrophil aggregation and platelet mitochondria number under normal and hyperglycaemic conditions in vitro using human samples (from healthy individuals and diabetic patients) and a neutrophil-like cell culture model. As part of a human study or using animal models, the student will investigate the sustained effect of long-term exposure to polyphenols on thromboinflammatory markers and clot phenotype.</p> <h5>Training</h5> <p>The candidate will have access to the research facilities at the Leeds Institute of Cardiovascular and Metabolic Medicine (LICAMM) and will be trained in well-established techniques to investigate platelet physiology and clot structure. In addition, for in vitro work, the candidate will be trained on culturing and maintenance of cells and processing of human blood samples. Furthermore, the candidate will also be given the opportunity to receive training to work with animals for in vivo work, in accordance with Home Office regulations. The candidate will have the advantage of joining a multidisciplinary team, composed of researchers in the field of thrombosis and food science, to learn skills and obtain knowledge from both areas.</p> <h5>References</h5> <p>Maiocchi S, Alwis I, Wu MCL, Yuan Y, Jackson SP. Thromboinflammatory functions of platelets in ischemia-reperfusion injury and its dysregulation in diabetes. Semin Thromb Hemost, 2018; 44(2): p. 102-113.</p> <p>Blokhin IO, Lentz SR. Mechanisms of thrombosis in obesity. Curr Opin Hematol, 2013; 20(5): p. 437-44.</p> <p>Ariens RA. Fibrin(ogen) and thrombotic disease. J Thromb Haemost, 2013; 11 p. 294-305.</p> <p>Xu RG, Gauer JS, Baker SR, Slater A, Martin EM, McPherson HR, Duval C, Manfield IW, Bonna AM, Watson SP, et al. Gpvi (glycoprotein vi) interaction with fibrinogen is mediated by avidity and the fibrinogen αc-region. Arterioscler Thromb Vasc Biol, 2021; 41(3): p. 1092-1104.</p> <p>Selders GS, Fetz AE, Radic MZ, Bowlin GL. An overview of the role of neutrophils in innate immunity, inflammation and host-biomaterial integration. Regen Biomater, 2017; 4(1): p. 55-68.</p> <p>Papayannopoulos V. Neutrophil extracellular traps in immunity and disease. Nat Rev Immunol, 2018; 18(2): p. 134-147.</p> <p>Shi Y, Gauer JS, Baker SR, Philippou H, Connell SD, Ariëns RAS. Neutrophils can promote clotting via fxi and impact clot structure via neutrophil extracellular traps in a distinctive manner in vitro. Sci Rep, 2021; 11(1): p. 1718.</p> <p>Ramirez GA, Manfredi AA, Maugeri N. Misunderstandings between platelets and neutrophils build in chronic inflammation. Front Immunol, 2019; 10: p. 2491.</p> <p>Shan Z, Li Y, Baden MY, Bhupathiraju SN, Wang DD, Sun Q, Rexrode KM, Rimm EB, Qi L, Willett WC, et al. Association between healthy eating patterns and risk of cardiovascular disease. JAMA Intern Med, 2020; 180(8): p. 1090-1100.</p> <p>Kerimi A, Nyambe-Silavwe H, Pyner A, Oladele E, Gauer JS, Stevens Y, Williamson G. Nutritional implications of olives and sugar: Attenuation of post-prandial glucose spikes in healthy volunteers by inhibition of sucrose hydrolysis and glucose transport by oleuropein. Eur J Nutr, 2019; 58(3): p. 1315-1330.</p> <p>Heptinstall S, May J, Fox S, Kwik-Uribe C, Zhao L. Cocoa flavanols and platelet and leukocyte function: Recent in vitro and ex vivo studies in healthy adults. J Cardiovasc Pharmacol, 2006; 47(Suppl 2): p. S197-S205.</p> <p>Houghton MJ, Kerimi A, Tumova S, Boyle JP, Williamson G. Quercetin preserves redox status and stimulates mitochondrial function in metabolically-stressed hepg2 cells. Free Radic Biol, 2018; 129: p. 296-309.</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 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>