LICAMM Developing small molecule therapeutics to target cardiac inflammation and disease

Summary

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.

Toll-like receptors (TLRs) are a family of pattern recognition receptors involved in cardiovascular disease. Importantly, studies have demonstrated that Toll-like receptor 4 (TLR4) activates the expression of several of pro-inflammatory cytokine genes that play pivotal roles in cardiac inflammation.

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.

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.

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’s overall inflammatory response.

References

1. 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
2. Midwood, K.S., Orend, G. The role of tenascin-C in tissue injury and tumorigenesis. J. Cell Commun. Signal. 3, 287–310 (2009). https://doi.org/10.1007/s12079-009-0075-1
3. Maqbool A, Spary EJ, Manfield IW et al. 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.
4. 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

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.

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.