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Molecular mechanism of innate immunity mediated by the Toll/IL1 receptor signalling pathways


   Department of Biochemistry

  Prof N J Gay  Applications accepted all year round  Competition Funded PhD Project (Students Worldwide)

About the Project

Our research aims to elucidate the molecular and cellular regulation of innate immune signal transduction in the context of infectious, inflammatory and autoimmune disease. We focus on the Toll-like receptors that respond to pathogen associated molecules such as lipopolysaccharide and non-self nucleic acids. A second strand of our research is the functional and evolutionary inter-relationships in the ontogeny of the nervous and immune systems. We focus on the function of Toll receptors in invertebrate neurogenesis and the role of signaling by Toll-like receptors (TLRs) and LRRK2 in vertebrate microglia for the initiation and progression of neurodegenerative diseases, especially Parkinson’s. We published high impact papers showing that in Drosophila Toll receptors fulfill the function of neurotrophins in the insect nervous system. Our future research aims are to use cutting edge techniques in single molecule imaging of live cells, biophysics, structural and cell biology to elucidate the kinetics, dynamics and cooperativity of inflammatory signaling.


References

1. Latty, S. L., Sakai, J., Hopkins, L., Verstak, B., Paramo, T., Berglund, N. A., Cammorota, E., Cicuta, P., Gay, N. J., Bond, P. J., Klenerman, D., and Bryant, C. E. (2018) Activation of Toll-like receptors nucleates assembly of the MyDDosome signaling hub. Elife 7, 31377.
2. Pizzuto, M. Lonez, C., Gangloff, M. Tourlomousis, P., Pelegrín, P., Ruysschaert, J-M., Gay N.J. and Bryant, C.E. (2019) Saturation of cardiolipin acyl chains flips Toll-like receptor-4 activity from antagonist to agonist. Cell Mol Life Sci.76, 3679-3680.
3. Levy, D., Tourlomousis, P., Hopkins, L., Symmons, M.F., Bryant, C.E. (2019). Parkinson’s disease associated kinase LRRK2 regulates the expression of genes required for cell adhesion, motility and chemotaxis in activated macrophages.in press. J Biol Chem
4. Gay, N. J. (2019) Role of self-organising myddosome oligomers in inflammatory signalling by Toll-like receptors. BMC Biol 17, 15.
5. Sardinha-Silva, A., Pinzan, C., Mendonça-Natividade, F.C., Lopes, C. D., Costa, D. l., Jacot, D., Fernandes, F.F., Zorzetto-Fernandes, A., Gay, N.J., Sher, A., Jankovic, D., Soldati-Favre, D., Grigg, M.E., Roque-Barreira, M.C. (2019) The lectin-specific activity of Toxoplasma gondii microneme proteins 1 and 4 binds Toll-like receptor 2 and 4 N-glycans to regulate innate immune priming. PLoS Path 15, e1007871.
6. Moncrieffe, M., Bollschweiler D., Li, B., Penczek, P.A. Hopkins, L., Bryant, C. E. David Klenerman, D and Gay, N.J. (2019) MyD88 death domain oligomerisation determines Myddosome architecture: Implications for TLR signalling. Structure, in press.
7. Lauenstein, J.U., Udgata, A., Bartram, A., De Sutter, D., Fisher, D., Halabi, S., Eyckerman, S. and Gay N.J. (2019) Phosphorylation of the multi functional signal transducer B-cell adaptor protein (BCAP) facilitates recruitment of multiple SH2/SH3 proteins including Grb2. J Biol Chem jbc.RA119.009931. doi:10.1074/jbc.RA119.009931.

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