Mechanosensing and Mitral Valve Prolapse: from the Molecular Mechanisms to the Progression of the Disease

Informations projet

MechanoMVP

N° de convention de subvention: 846291

DOI

10.3030/846291

Projet clôturé

Date de signature de la CE 16 Avril 2019

Date de début 1 Mai 2019

Date de fin 30 Octobre 2021

Financé au titre de

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Coût total

€ 196 707,84

Contribution de l’UE

€ 196 707,84

Coordonné par

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
France

Periodic Reporting for period 1 - MechanoMVP (Mechanosensing and Mitral Valve Prolapse: from the Molecular Mechanisms to the Progression of the Disease)

Période du rapport: 2019-05-01 au 2021-04-30

Résumé du contexte et des objectifs généraux du projet

Mitral valve prolapse (MVP) is the most frequent form of degenerative mitral valve (MV) disease and is a major cause of cardiovascular morbidity and mortality. No medical therapy is currently available. Recent familial and population genetic studies have identified genes causally related to MVP, such as FLNA, encoding for Filamin A protein. These findings have paved the road to study mechanisms and signaling pathways involved in the development and progression of MVP that will then be useful to identify potential therapeutic targets and thus limit the use of cardiac surgery. This relies on two complementary approaches: comprehensive phenotyping of the FLNA-MVP patients and the implementation of experimental models.

In the MechanoMVP project, I propose to identify and study the pathophysiological mechanisms and regulation of signaling pathways involved in the development and progression of MVP based on the comprehensive analysis of the unique knock-in rat model for FLNA-P637Q mutation recently developed at the host institution.

Over the action, I generated landmark data in the field of MVP, by identifying main signaling pathways involved in the development of MVP (data currently submitted for publication). I pursued this work by studying one of the main pathways identified in order to dissect the specific pathophysiological mechanisms and identify potential therapeutic targets. In conclusion, the action provide unique validation of potential therapeutic targets, with important translational potential due the physiological and integrated models used in the project.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

I first confirmed the relevance of our new and unique animal model generated at the host institution. Using multimodal imaging approaches, including classical echocardiography and histology, as well as a new and innovative approach relying on computed tomography I developed at the host institution, I confirm the presence of MVP and then the relevance of our model to study pathophysiological mechanisms and signaling pathways.
Following this validation, I performed a molecular phenotyping of the mitral valve. Based on RNA-sequencing performed on the mitral valve from KI and WT animals (3-week old), I identified the main signaling pathways involved in the development of MVP. These landmark data in the field will open new avenues for the understanding of the disease and identify potential therapeutic targets.

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

With this project, I validated the pertinence of the first animal model mimicking human disease and thus opening a new avenue to better understand the disease and develop therapeutic approaches to limit the use of cardiac surgeries.

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