2026 Bhattacharya Group: Targeting chemokine inhibitors to the inflamed islet
- Shoumo Bhattacharya
About the Research
Therapeutics affecting T-cell function are effective in type 1 diabetes (T1D) but cause systemic immunosuppression. Reducing T-cell ingress to islets is an alternative strategy that could minimize such side effects. As several CC and CXC-class chemokines drive T-cell migration, their redundancy has foiled therapeutic development. We have identified two novel peptides, CM304 and CM1629 that bind multiple CC and CXC-chemokines and inhibit T-cell migration against a pool of inflamed islet chemokines. To avoid systemic side effects, we need to limit CM304/CM1629 peptide action to islets. We hypothesise that CM304 or CM1629 can be conjugated to "islet ZIP-codes" to create agents that have both islet-targeting and T-cell migration inhibition activity. We aim to a) develop peptides binding to an islet-specific extracellular protein as candidate "islet ZIP-codes"; b) conjugate validated "islet ZIP-codes" to CM304 and CM1629 using click-chemistry and confirm that they retain both "islet ZIP code" activity and the ability to inhibit chemokine-induced T-cell migration. The anticipated outcome of this project will be agents that would be predicted to specifically reduce T-cell ingress to the islet in type 1 diabetes. These agents could be taken forward into animal models of type 1 diabetes.
This project is not suitable for part-time study.
Training Opportunities
Bhattacharya lab: phage display, bioinformatics, chemokine biology, CD8/CD4-T-cell generation and cell migration assays
Hodson lab: human islet culture, microscopy, functional assays
Brennan lab: peptide synthesis, microscale thermophoresis
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.
Additional Supervisors
1. David Hodson
2. Paul Brennan
Publications
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1 |
Kryukova, J., Vales, S., Payne, M., Smagurauskaite, G., Chandra, S., Clark, C.J., Davies, G. & Bhattacharya, S. Development of chemokine network inhibitors using combinatorial saturation mutagenesis. Commun Biol 8, 549 (2025) PMID:40181178. |
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2 |
Vales, S., Kryukova, J., Chandra, S., Smagurauskaite, G., Payne, M., Clark, C.J., Hafner, K., Mburu, P., Denisov, S., Davies, G., Outeiral, C., Deane, C.M., Morris, G.M. & Bhattacharya, S. Discovery and pharmacophoric characterization of chemokine network inhibitors using phage-display, saturation mutagenesis and computational modelling. Nat Commun 14, 5763 (2023) PMID:37717048. |
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3 |
Ast, J., Nasteska, D., Fine, N.H.F., Nieves, D.J., Koszegi, Z., Lanoiselée, Y., Cuozzo, F., Viloria, K., Bacon, A., Luu, N., Newsome, P.N., Calebiro, D., Owen, D.M., Broichhagen. J.*, Hodson, D.J.* (2023). Revealing the tissue-level complexity of endogenous glucagon-like peptide-1 receptor expression and signaling. Nat Commun. 18;14(1):301. *Corresponding authors. |
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4 |
de Bray, A. Roberts, A.G., Armour, S., Tong, J., Huhn, C., Gatin-Fraudet, B., Roßmann, K., Shilleh, A.H., Jiang, W., Figueredo Burgos, N.S., Trott, J.P.P., Viloria, K., Nasteska, D., Pearce, A., Miyazaki, S., Tomlinson, J.W., Owen, D.M., Nieves, D.J., Ast, J., Cyranka, M., Epanchintsev, A., Ämmälä, C., Reimann, F., Soykan, T., Ladds, G., Adriaenssens, A.E.A., Trapp, S., Jones, B., Broichhagen, J.,* Hodson, D.J.* (2025). Fluorescent GLP1R/GIPR dual agonist probes reveal cell targets in the pancreas and brain. Nat Metab. Accepted. *Corresponding authors. |
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5 |
Vazquez-Rodriguez, S.; Wright, M.; Rogers, C.; Cribbs, A.; Velupillai, S.; Philpott, M.; Lee, H.; Dunford, J.; Huber, K.; Robers, M.; Vasta, J.; Thezenas, M.; Bonham, S.; Kessler, B.; Bennett, J.; Fedorov, O.; Raynaud, F.; Donovan, A.; Blagg, J.; Bavetsias, V.; Oppermann, U.; Bountra, C.; Kawamura, A.; Brennan, P. Design, Synthesis and Characterization of Covalent KDM5 Inhibitors. Angewandte Chemie: International Edition 2018, 58 (2), 515–519. https://doi.org/10.1002/anie.201810179. |
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Frank, N.; Nugent, J.; Shire, B.; Pickford, H.; Rabe, P.; Sterling, A.; Zarganes-Tzitzikas, T.; Grimes, T.; Thompson, A.; Smith, R.; Schofield, C.; Brennan, P.; Duarte, F.; Anderson, E. Synthesis of Meta-Substituted Arene Bioisosteres from [3.1.1]Propellane. Nature 2022, 611, 721–726. https://doi.org/10.1038/s41586-022-05290-z |