3 year PhD position at Université Grenoble Alpes (IBS), France, one of Instruct-ERIC Centres.
Title of the PhD project: CALCinf - Complement C1 and HMGB1 Alarmin Crosstalk in Inflammation
PhD supervisors: Véronique Rossi - veronique.rossi@ibs.fr & Thierry Rabilloud - thierry.rabilloud@cnrs.fr
Grenoble host laboratory: Institut de Biologie Structurale (IBS), Gaboriaud’s team in the CAID group ; in collaboration with the ProMIT team, Chemistry and Biology of Metals laboratory (CBM).
Project summary:
Complement C1 and the Alarmin HMGB1 are two actors of the immune surveillance. Their regulation processes and crosstalk play antagonistic roles in the onset of their inflammatory response. The interaction of C1q, the recognition defense collagen of C1, with HMGB1 has been described recently in two different molecular complexes. On one hand C1q can interact directly with HMGB1 and might activate the classical complement pathway, leading to pro-inflammatory responses. On an other hand, HMGB1 also interacts with C1q but in a macro complex involving two immune receptors (RAGE and LAIR1) at the macrophage surface, leading to the silencing of the pro inflammatory HMGB1/RAGE effect. Moreover, a third HMGB1 crosstalk with C1s, i.e. the protease associated with C1q in the C1 complex, has been shown to be associated to chronic inflammatory diseases such as Lupus or periodontal Ehlers Danlos syndrome. All these crosstalks between HMGB1 and complement C1 proteins appeared recently in the litterature and need further investigation for a better understanding of their balanced roles in the inflammatory response. The aim of this PhD thesis is therefore to elucidate their interconnection in the three different systems described above. For that, the PhD student will use two parallel approaches from the two partners laboratories. A molecular dissection approach using soluble fragments and mutants of the protein actors of the three systems will be performed in the IBS team and will be tested concomitantly in the CBM team for their modulation of the macrophages responses.
Required skills:
Master degree in cell biology, biochemisty, protein engineering, immunology.
Student role:
The PhD student will be involved in all the experimental processes described above, from protein engineering design and sample production and cellular testing (molecular biology, cellular biology, biochemistry, protein expression, sample purification by chromatography and sample quality controls, macrophages tests for cytokines and phagocytosis), to experimental design as well as data processing
and presentation of the results. The student will be involved in writing manuscripts for publication in peer-reviewed journals.
Keywords :
Complement C1, Alarmin HMGB1, Crosstalk, Inflammation balance, Macrophages
Relevant publications of the teams :
IBS-CAID team :
Jacquet M, Cioci G, Fouet G, Bally I, Thielens NM, Gaboriaud C, Rossi V. C1q and Mannose-Binding Lectin Interact with CR1 in the Same Region on CCP24-25 Modules. Front Immunol (2018) 9:453. doi:10.3389/fimmu.2018.00453
Bally I, Dalonneau F, Chouquet A, Gröbner R, Amberger A, Kapferer-Seebacher I, Stoiber H, Zschocke J, Thielens NM, Rossi V, and Gaboriaud C. Two Different Missense C1S Mutations, Associated to Periodontal Ehlers-Danlos Syndrome, Lead to Identical Molecular Outcomes. Front Immunol (2019) 10:2962. doi:10.3389/fimmu.2019.02962
Fouët G, Bally I, Signor L, Häußermann K, Thielens NM, Rossi V and Gaboriaud C. Headless C1q: a new molecular tool to decipher its collagen‐like functions. FEBS J (2020) febs.15543. doi:10.1111/febs.15543
Fouët G, Gout E, Wicker-Planquart C, Bally I, De Nardis C, Dedieu S, Chouquet A, Gaboriaud C, Thielens NM, Kleman J-P, and Rossi V. Complement C1q Interacts With LRP1 Clusters II and IV Through a Site Close but Different From the Binding Site of Its C1r and C1s-Associated Proteases. Front Immunol (2020) 11: doi:10.3389/fimmu.2020.583754
CBM-ProMIT team :
Dalzon, B., Guidetti, M., Testemale, D., Reymond, S., Proux, O., Vollaire, J., Collin-Faure, V., Testard, I., Fenel, D., Schoehn, G., Arnaud, J., Carriere, M., Josserand, V., Rabilloud, T*., Aude- Garcia, C. Utility of macrophages in an antitumor strategy based on the vectorization of iron oxide nanoparticles. Nanoscale. (2019) 11(19): p. 9341-9352. doi: 10.1039/c8nr03364a.
Dalzon, B., Aude-Garcia, C, Diemer, H., Bons, J., Marie-Desvergne, C., Pérard, J., Dubosson, M., Collin-Faure, V., Carapito, C., Cianferani, S., Carriere, M., Rabilloud, T., The longer the worse: a combined proteomic and targeted study of the long-term versus short-term effects of silver nanoparticles on macrophages. Environmental Science: Nano. (2020) 7(10): p. 2032-2046. doi: 10.3390/proteomes7020026.
Torres, A., Dalzon, B., Collin-Faure, V., Rabilloud, T. Repeated vs. Acute Exposure of RAW264.7 Mouse Macrophages to Silica Nanoparticles: A Bioaccumulation and Functional Change StudyNanomaterials. (2020) 10(2):215 doi: 10.3390/nano10020215.
Application deadline: 30th April 2021
