Rho protein signaling and target discovery in vascular and pulmonary diseases
Vincent Sauzeau, Gervaise Loirand, Thibaut Quillard
Investigators : Dorian Hassoun, Gervaise Loirand, Thibaut Quillard, Vincent SauzeauPhD Students : Hugo Bergereau, Marc Rio
Support staff : Morgane Rousselle
Airway hyperresponsiveness (AHR) and pulmonary remodeling are hallmarks of asthma. The molecular mechanisms regulating airway smooth muscle cells (aSMC) contraction and proliferation involved in severe asthma are still largely unknown. Recently, we identified a new signaling pathway of regulation of intracellular Ca2+ by the small GTPase Rac1 that plays an essential role in aSMC bronchoconstriction (André et al. JACI 2018). In addition, we demonstrated that (i) Rac1 is activated in airways from mouse models of asthma, and (ii) the specific deletion of the Rac1 gene in smooth muscle cells prevents AHR and bronchial muscularization. Rac1 signaling thus appears as a new attractive therapeutic target in asthma. The challenge of this project is to translate our original findings and "proof-of-concept" from mice models of asthma to human disease and to evaluate the therapeutic potential of inhibiting the Rac1 signaling pathway in severe asthma patients.
Three research axes have been initiated to achieve these objectives :
- Assessment of the expression and activity of Rac1 in airway smooth muscle of asthmatic patients
- Identification of Rac1 activators in asthma
Activation of Rac1 (corresponding to the switch from a GDP-bound state to a GTP-bound state) requires a guanine nucleotide exchange factor (Rac GEF) that catalyzes GDP to GTP exchange. The Rac GEF(s) responsible for the over-activity of Rac1 in asthma thus represent potentially valuable therapeutic targets. We will set up biochemical and proteomic approaches to identify Rac1 GEF activated in aSMC during asthma in allergic asthma experimental model (house dust mite-sensitized mice) and human biopsies, and assess their role in the development of the disease.
- Discovery and development of new Rac1 inhibitors
A Rac-specific competitive inhibitor of guanine nucleotide binding reduces metastasis in triple-negative breast cancer. Dilasser F, Rose L, Quemener A, Ferrandez Y, Hassoun D, Rousselle M, Bergereau H, Lambot SM, Anselmino LE, Trouillet C, Andre G, Maillasson M, Croyal M, Riviere M, Dubreuil D, Collet S, Souaze F, Campone M, Patsouris A, Mortier E, Marquez MM, Juin P, Lebreton J, Tessier A, Cherfils J, Loirand G, Sauzeau V. Cell Rep Med. 2025 Jul 15;6(7):102233. doi: 10.1016/j.xcrm.2025.102233. Epub 2025 Jul 8.
Impact of Rac1 activation on eosinophil degranulation in severe asthma. Bergereau H, Hassoun D, Marquant Q, Rousselle M, Magnan A, Loirand G, Sauzeau V. Rev Mal Respir. 2025 Mar;42(3):121-124. doi: 10.1016/j.rmr.2025.02.006. Epub 2025 Feb
Bronchial smooth muscle cell in asthma: where does it fit ? Hassoun D, Rose L, Blanc FX, Magnan A, Loirand G, Sauzeau V. BMJ Open Respir Res. 2022 Sep
Smooth muscle Rac1 contributes to pulmonary hypertension. Dilasser F, Rio M, Rose L, Tesse A, Guignabert C, Loirand G, Sauzeau V. Br J Pharmacol. 2022 Jul;179(13):3418-3429. doi: 10.1111/bph.15805. Epub 2022 Feb 24.
Essential role of smooth muscle Rac1 in severe asthma associated-airway remodeling. Dilasser F, Rose L, Hassoun D, Klein M, Rousselle M, Brosseau C, Guignabert C, Taille C, Dombret MC, Di-Candia L, Heddebaut N, Bouchaud G, Pretolani M, Magnan A, Loirand G, Sauzeau V. Thorax. 2021
Patents
- "Methods and Pharmaceutical composition for inducing bronchodilatation". V. Sauzeau et al. (PCT/EP2014/062402)
- "Inhibitors of rac1 and uses thereof for inducing bronchodilatation." V. Sauzeau et al. (EP17305662)
Funding
- Agence National pour la Recherche
- Fondation du Souffle
