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Therapeutic targeting of chemokines in inflammation


Radcliffe Department of Medicine

About the Project

Inflammation, driven by leucocytes, adversely affects organ function in diseases such as myocarditis, myocardial infarction, acute lung injury, sepsis and pancreatitis, . Chemokines are a family of >40 proteins secreted in response to disease- and pathogen-associated molecular patterns. They bind to GPCRs expressed on leucocytes causing their directed migration (chemotaxis) to sites of inflammation. The high total chemokine load in disease, promiscuity of receptor expression and receptor-chemokine interactions, together with feedforward loops render the chemokine network robust. Targeting individual chemokines or receptors has failed as a strategy in inflammatory disease. Ticks inject chemokine-binding proteins called evasins, which inhibit inflammation, and allow the tick to feed for days to weeks.
Over 40 evasins have been characterized by us and others to date that have broad and promiscuous chemokine binding properties. As a result, they are potently active in vitro and in inflammatory disease models, and have potential as biological therapeutics. We have improved on nature by combining these evasins to create “multi-warhead evasins” that extend their ability to block chemokines, and have shown that these are active in vivo. In a recent development we have identified small peptides derived from an evasin that mimic the evasin function both in vitro and in vivo.

Over the next five years, funded by BHF Program, Project and Centre for Regenerative Medicine Grants we will study their effects in preclinical models of myocarditis and of myocardial infarction. We will also develop pre-clinical models of inflammation in organs such as lungs, and of systemic inflammation. We will develop methods to monitor inflammation in vivo including leucocyte imaging with optical tracers and radiotracers (e.g. SPECT), and use these to assess efficacy of the new evasins. We will use approaches such as phage-display combined with NextGen sequencing to systematically identify new evasin-derived peptides that could be used as therapeutic agents.


Training Opportunities
Depending on the nature of the project, specific training will be provided in in vitro approaches to produce and characterize evasins (molecular cloning, protein expression & purification, biolayer interferometry, chemotaxis assays, flow cytometry, phage display, NextGen sequencing), training in in vivo approaches including models of inflammation (short term e.g. zymosan air-pouch, and longer term e.g. myocarditis, myocardial infarction, acute lung injury), methods to image inflammation and leucocyte trafficking in vivo (e.g. leucocyte imaging) and analysis of inflammation in tissues using flow cytometry and histopathology. These approaches will be used to characterize the efficacy of the evasins in inhibiting inflammation in vivo.

Students are encouraged to attend the MRC Weatherall Institute of Molecular Medicine DPhil Course, which takes place in the autumn of their first year. Running over several days, this course helps students to develop basic research and presentation skills, as well as introducing them to a wide-range of scientific techniques and principles, ensuring that students have the opportunity to build a broad-based understanding of differing research methodologies.

Generic skills training is offered through the Medical Sciences Division’s Skills Training Programme. This programme offers a comprehensive range of courses covering many important areas of researcher development: knowledge and intellectual abilities, personal effectiveness, research governance and organisation, and engagement, influence and impact. Students are actively encouraged to take advantage of the training opportunities available to them.

As well as the specific training detailed above, students will have access to a wide-range of seminars and training opportunities through the many research institutes and centres based in Oxford.

The Department has a successful mentoring scheme, open to graduate students, which provides an additional possible channel for personal and professional development outside the regular supervisory framework. We hold an Athena SWAN Silver Award in recognition of our efforts to build a happy and rewarding environment where all staff and students are supported to achieve their full potential.

Funding Notes

Funding for this project is available to scientists through the RDM Scholars Programme, which offers funding to outstanding candidates from any country. Successful candidates will have all tuition and college fees paid and will receive a stipend of £18,000 per annum.

For October 2021 entry, the application deadline is 8th January 2020 at 12 noon midday, UK time.

Please visit our website for more information on how to apply.

References

Singh, K., Davies, G., Alenazi, Y., Eaton, J. R. O., Kawamura, A., and Bhattacharya, S. (2017) Yeast surface display identifies a family of evasins from ticks with novel polyvalent CC chemokine-binding activities. Sci Rep 7, 4267

Alenazi, Y., Singh, K., Davies, G., Eaton, J. R. O., Elders, P., Kawamura, A., and Bhattacharya, S. (2018) Genetically engineered two-warhead evasins provide a method to achieve precision targeting of disease-relevant chemokine subsets. Sci Rep 8, 6333

Eaton, J. R. O., Alenazi, Y., Singh, K., Davies, G., Geis-Asteggiante, L., Kessler, B., Robinson, C. V., Kawamura, A., and Bhattacharya, S. (2018) The N-terminal domain of a tick evasin is critical for chemokine binding and neutralization and confers specific binding activity to other evasins. J Biol Chem 293, 6134-6146.

Lee, A.W., Deruaz, M., Lynch, C., Davies, G., Singh, K., Alenazi, Y., Eaton, J.R.O., Kawamura, A., Shaw, J., Proudfoot, A.E.I., Dias, J.M. & Bhattacharya, S. A knottin scaffold directs the CXC-chemokine-binding specificity of tick evasins. Journal of Biological Chemistry 294, 11199-11212 (2019).

Darlot, B., Eaton, J.R.O., Geis-Asteggiante, L., Yakala, G.K., Karuppanan, K., Davies, G., Robinson, C.V., Kawamura, A. & Bhattacharya, S. Engineered anti-inflammatory peptides inspired by mapping an evasin-chemokine interaction. The Journal of biological chemistry (2020).

Bhusal, R.P., Eaton, J.R.O., Chowdhury, S.T., Power, C.A., Proudfoot, A.E.I., Stone, M.J. & Bhattacharya, S. Evasins: Tick Salivary Proteins that Inhibit Mammalian Chemokines. Trends Biochem Sci 45, 108-122 (2020).

Bhattacharya S, Kawamura A, Using Evasins to Target the Chemokine Network in Inflammation A. Adv. Protein Chem. Struct. Biol. 2019, in press.

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