Thrombin and thrombin receptor as main players in the crosstalk between coagulation and inflammation in a model of peripheral nerve injury

Proponente Cinzia Fabrizi - Professore Associato
Sottosettore ERC del proponente del progetto
Componenti gruppo di ricerca
Componente Categoria
Elena Pompili Componenti strutturati del gruppo di ricerca
Elena De Santis Componenti strutturati del gruppo di ricerca
Componente Qualifica Struttura Categoria
Stefano Leone collaboratore tecnico Dipartimento di Scienze - Università di Roma Tre Altro personale aggregato Sapienza o esterni, titolari di borse di studio di ricerca
Peter James Brophy Full Professor University of Edinburgh - UK Altro personale aggregato Sapienza o esterni, titolari di borse di studio di ricerca

Inflammation and coagulation are two main host-defence systems interacting with each other. Inflammation activates coagulation and coagulation modulates the inflammatory activity at different levels. Disturbances of their interplay significantly contribute to many human diseases.
Local inflammation and oxidative stress together with the scar formation at the lesion site are the most common pathways known to limit peripheral nerve regeneration. The failure in the regeneration of injured peripheral nerves can lead to motor and sensory deficits ending with paralysis and chronic pain of the affected areas. After peripheral nerve injury the activity of thrombin, the key mediator of coagulation, is known to rapidly rise partially coming from blood extravasation but also being locally generated.
Our previous data indicate that thrombin can favour or limit neural regeneration according to its concentration acting through its main receptor, the protease activated receptor 1 (PAR1). PAR1 is expressed in Schwann cells especially at the level of the nodes of Ranvier (Pompili et al., 2017; Pompili et al., 2020). Axonal regeneration in peripheral nerves is greatly supported by Schwann cells that after injury de-differentiate and guide axons to their original target tissue.
The present research project aims to analyse how different levels of thrombin affect the ability of Schwann cells to execute the autophagic removal of myelin and the production of inflammatory mediators in rodent primary cultures and ex vivo nerve explants. Our hypothesis is that thrombin acting through the JNK/c-Jun pathway affects the efficiency of the autophagic flux regulating myelin removal and the production of the pro-inflammatory mediator MIF (macrophage migration inhibitory factor) in Schwann cells. Our study will also consider the effect of different levels of thrombin on the proliferation of peripheral nerve fibroblasts since these cells are the main responsible of the scar formation after injury.

LS5_1, LS5_3, LS1_10

© Università degli Studi di Roma "La Sapienza" - Piazzale Aldo Moro 5, 00185 Roma