PROJECT: JTC2022 - Cerebrovascular: MECACCM

Preclinical study targeting mechanosensitive calcium channels for Cerebral Cavernous Malformations therapy and early diagnosis.

Abstract

Cerebral Cavernous Malformations (CCM), a cerebrovascular disease affecting small vessels in 1/ 200 individuals, are stacks of dilated and haemorrhagic venous capillaries formed by a unique layer of poorly joined endothelial cells. Incompetent blood-brain barrier (BBB) is a major manifestation of CCM leading to headaches, seizures, paralysis, sensory or cognitive deficits. Currently, surgical resection is not always possible and there is no therapeutic alternative. MECACCM will explore molecular events at the onset of CCM and innovative therapeutic strategies. Mysteriously, CCM lesions form only in low flow venous capillaries but not in high flow vessels. Preliminary results from our consortium advocate for a causative role of mechanosensitive calcium channels of the Piezo and TRPV families. Their contributions to CCM onset has however never been explored. This project brings together recognized experts in endothelial mechanotransduction, cell and matrix mechanics and miRNA signalling to investigate the interplay between cell-generated forces, intrinsic molecular pathways and extrinsic mechanical cues. By combining in vitro data with the analysis of patient CCM samples collected in the largest German biobank, the goal of this project is to identify early biomarkers of CCM initiation and to perform preclinical testing of drugs targeting mechanosensitive calcium channels in an in vivo CCM mouse model thanks to experts in nanomedicine and functional neuroimaging of the BBB.

Keywords

Omics approaches Imaging techniques Molecular modelling techniques Pharmacology Animal studies

Call topic

Cerebrovascular

Proposed runtime

n/a - n/a

Project team

Eva Faurobert (Coordinator)
France (ANR)
Hans Van Oosterwyck
Belgium (FWO)
Souvik Kar
Germany (BMBF)
Luigi Battaglia
Italy (other)
Emmanuel Barbier
France (ANR)
Adriana Duris Adameova
Slovakia (SAS)