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

Projektbeschreibung

Umfassende Studien zur Entstehung und Progression des Mitralklappenprolaps

Der Mitralklappenprolaps ist die am häufigsten auftretende Form der degenerativen Mitralklappenerkrankung und eine der Hauptursachen kardiovaskulärer Morbidität und Mortalität. Bei genetischen Untersuchungen der Population wurden Gene identifiziert, die am nichtsyndromischen Mitralklappenprolaps beteiligt sind, darunter das FLNA-Gen, das für das Filamin-A-Protein kodiert. Im Rahmen des EU-finanzierten Projekts MechanoMVP werden die stressbedingten Mechanismen sowie die Regulation der an der Entstehung und Progression des Mitralklappenprolaps beteiligten Signalwege untersucht, um potenzielle therapeutische Zielstrukturen aufzuzeigen. Die Forschung umfasst eine umfangreiche Analyse des einzigartigen Knock-in-Rattenmodells für die FLNA-P637Q-Mutation und der damit verbundenen Klappenzellmodelle mithilfe von Phänotypisierung, multimodaler Bildgebung und biochemischen Ansätzen in Verknüpfung mit zellulären und molekularen Analysen.

Ziel

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. Familial and population genetic studies have identified genes causally related to non-syndromic 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. This relies on two complementary approaches: a comprehensive phenotyping of the FLNA-MVP patients and the implementation of experimental models.
In the MechanoMVP project, I propose to study stress-related 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, as well as the related-cellular models, recently developed at the host institution.
The specific actions I will conduct through this project are the comprehensive phenotyping of the unique rat model using multimodality imaging and biochemical approaches coupled with the cellular and molecular analyses done on mutant and WT valvular cell models.
Based on this integrative approach mixing genetics, pathophysiological and mechanistic experimentations, and a multimodality/gold standard imaging phenotyping, MechanoMVP will provide landmark data in the field of MVP. In the context of a frequent CV pathology increasing with age and the rapid aging of the population, MVP and its ensuing adverse CV events will exponentially grow in the coming next years. With the only use of surgery to “treat” MVP patients, this disease will considerably increase the health care and socio-economic burden. MechanoMVP will open new avenues for the development of therapeutic approaches.