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

Descrizione del progetto

Studi comprensivi sull’origine e sulla progressione del prolasso mitralico

Il prolasso mitralico è la forma più comune di malattia degenerativa della valvola mitrale, nonché una delle cause principali di morbilità e mortalità cardiovascolare. Gli studi genetici sulla popolazione hanno identificato i geni coinvolti nel prolasso mitralico non sindromico, tra cui figura il gene FLNA che codifica la proteina filamina A. Il progetto MechanoMVP, finanziato dall’UE, sta studiando i meccanismi correlati allo stress e la regolazione delle vie di segnalazione coinvolte nello sviluppo e nella progressione del prolasso mitralico per identificare potenziali bersagli terapeutici. La ricerca comprende un’analisi comprensiva del modello unico di topo knock-in per la mutazione FLNA-P637Q e dei modelli correlati di cellule valvolari attraverso la fenotipizzazione, l’imaging multimodalità e gli approcci biochimici accoppiati ad analisi cellulari e molecolari.

Obiettivo

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.