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Developing small molecule therapeutics to target cardiac inflammation and disease

PGR-P-1018

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Key facts

Type of research degree
4 year PhD
Application deadline
Ongoing deadline
Country eligibility
International (outside UK)
Funding
Non-funded
Supervisors
Dr Azhar Maqbool and Dr Katie Simmons
Schools
School of Medicine
Research groups/institutes
Leeds Institute of Cardiovascular and Metabolic Medicine
<h2 class="heading hide-accessible">Summary</h2>

Inflammation plays an important role in the wound healing response following cardiac injury. However, chronic uncontrolled inflammation is implicated in several cardiovascular diseases including myocarditis, myocardial infarction, ischemia-reperfusion injury and heart failure.

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

<p>Toll-like receptors (TLRs) are a family of pattern recognition receptors involved in cardiovascular disease. Importantly, &nbsp;studies have demonstrated that Toll-like receptor 4 &nbsp;(TLR4) activates the expression of several of pro-inflammatory cytokine genes that play pivotal roles in cardiac inflammation.&nbsp;</p> <p>Tenascin-C is an extracellular matrix protein that is induced upon tissue damage where it is thought to play a role in inflammation and wound healing. Recent studies have demonstrated that Tenascin C can react with TLR4 in the heart and may generate an autocrine loop of inflammation and so contribute to the persistence of inflammation observed in many cardiac disease.&nbsp;</p> <p>The aim of this project is to develop novel therapeutic strategies to target the FBG domain of TNC to abrogate the loop of non-resolving inflammation that leads to tissue destruction and fibrosis.&nbsp;</p> <p>This project will use a combination of techniques such as virtual high-throughput screening and ligand-based molecular modelling, in tandem with in vitro assays and in vivo models to identify inhibitors of FBG. These will ultimately facilitate development of therapeutics inhibiting the TNC-TLR4 interaction in chronic inflammatory based diseases. Inhibiting the TNC-TLR4 pathway in this way will have particular therapeutic value as its inhibition may provide new possibilities to reduce chronicity in distinct inflammatory diseases without curtailing the host&rsquo;s overall inflammatory response.</p> <h4>References</h4> <ol> <li>Yang, Y., Lv, J., Jiang, S. et al. The emerging role of Toll-like receptor 4 in myocardial inflammation. Cell Death Dis 7, e2234 (2016). https://doi.org/10.1038/cddis.2016.140&nbsp;</li> <li>Midwood, K.S., Orend, G. The role of tenascin-C in tissue injury and tumorigenesis. J. Cell Commun. Signal. 3, 287&ndash;310 (2009). https://doi.org/10.1007/s12079-009-0075-1&nbsp;</li> <li>Maqbool A, Spary EJ, Manfield IW et al. &nbsp;Tenascin C upregulates interleukin-6 expression in human cardiac myofibroblasts via toll-like receptor 4. World J Cardiol. 2016 May 26;8(5):340-50. doi: 10.4330/wjc.v8.i5.340.&nbsp;</li> <li>Goh FG, Piccinini AM, Krausgruber T et al. Transcriptional regulation of the endogenous danger signal tenascin-C: a novel autocrine loop in inflammation. J Immunol. 2010 Mar 1;184(5):2655-62. doi: 10.4049/jimmunol.0903359&nbsp;</li> </ol>

<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 minimum requirements for this programme in IELTS and TOEFL tests are: &bull; British Council IELTS - score of 7.0 overall, with no element less than 6.5 &bull; 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 Faculty Graduate School<br /> e:<a href="mailto:fmhpgradmissions@leeds.ac.uk">fmhpgradmissions@leeds.ac.uk</a>,</p>


<h3 class="heading heading--sm">Linked research areas</h3>