DS0403 - Exploration des systèmes et organes leur fonctionnement normal et pathologique : physiologie, physiopathologie, vieillissement

PAR2 signaling and associated therapeutic targets in inflammatory skin pathologies – PAR-2-PATH

Submission summary

The skin provides an impermeable barrier that plays a critical role in host defense. However, in many individuals, this barrier is compromised by genetic defects and/or environmental perturbations, which has been recognized as a critical trigger or exacerbation factor of inflammatory skin pathologies such as atopic dermatitis and Netherton syndrome. The molecular mechanisms governing the homeostatic maintenance of an impermeable skin barrier are incompletely defined. Identification of hallmarks of molecular deregulation common between skin diseases and amenable for pharmacological targeting could greatly assist rational design of drugs with the potential to benefit skin disease of both genetic and environmental origin.

A membrane tethered serine protease (MTSP) cascade was recently found to play vital roles in formation and maintenance of the skin barrier. Matriptase, its key player, also activates the G-protein coupled receptor PAR2 with unprecedented potency. Deregulation of MTSPs triggers inflammatory skin disease in mice, with PAR2 as a pivotal mediator. Deregulated kallikreins trigger skin disease in Netherton syndrome that is highly matriptase-dependent and PAR2-dependent in its inflammatory aspect. TSLP, a pro-Th2 cytokine that is sufficient to trigger atopic dermatitis-like disease, is induced by PAR2 when MTSPs or kallikreins are deregulated. We suspect that matriptase-PAR2 signaling plays a key role in inflammatory skin diseases, with TSLP as one downstream mediator. The goal of this project is to identify genetic and environmental causes of matriptase deregulation, dissect mechanisms of matriptase-induced pathology, develop in vivo and in vitro platforms to screen inhibitors of this signaling cascade, address matriptase deregulation in human inflammatory skin diseases, with the final aim to probe the potential of targeting PAR2 signaling for clinical benefit. While PAR2 appears to be a key mediator of MTSP driven pathology, it does not appear to contribute to their role in development of a functional skin barrier. Thus, PAR2 holds the promise to be a safe drug target.

To achieve these goals, we propose here a multi-faceted strategy ranging from molecular biology and signaling to the generation mouse models of human disease and analysis human skin samples by a consortium with complementary expertise, experimental models and human biobanks relevant to each facet of the project. This strategy is expected to have the breadth and rigor to establish the role of MTSP-PAR2-TSLP signaling in inflammatory skin diseases. Beyond insights into mechanistic understanding of diseases, the tools that will be generated and established in this project should provide valuable new in vitro and in vivo platforms for testing the efficacy and specificity of drugs targeting MTSP-PAR2-TSLP signaling, currently a limitation in the field. As the MTSP-PAR2 pathway is tightly regulated not only in epidermis, but also in other surface epithelia, lessons learnt from this project are likely to apply to other inflammatory diseases of barrier tissues, such as asthma and inflammatory bowel disease.

Project coordination

Eric CAMERER (Institut National de la Santé et de la Recherche Médicale)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

IGBMC Institut de Génétique et de Biologie Moléculaire et Cellulaire
INSTITUT PASTEUR
INSERM U1163 IHU IMAGINE Institut National de la Santé et de la Recherche Médicale
INSERM U970 Institut National de la Santé et de la Recherche Médicale

Help of the ANR 578,000 euros
Beginning and duration of the scientific project: September 2015 - 42 Months

Useful links

Explorez notre base de projets financés

 

 

ANR makes available its datasets on funded projects, click here to find more.

Sign up for the latest news:
Subscribe to our newsletter