Descrizione del progetto
Fattori di rischio associati allo sviluppo e al trattamento della stenosi valvolare aortica degenerativa
La stenosi valvolare aortica degenerativa è la malattia della valvola cardiaca più comune, che non prevede una terapia medica consolidata per arrestarne la progressione. L’unico trattamento disponibile consiste nella sostituzione transcatetere della valvola aortica (TAVR). Le mutazioni somatiche associate all’espansione dell’emopoiesi clonale sono legate a una prognosi sfavorevole per i pazienti con stenosi sottoposti a TAVR. Il progetto CHIP-AVS, finanziato dall’UE, si occuperà dei fattori di rischio associati allo sviluppo e al trattamento della stenosi valvolare aortica. Lo studio si concentrerà sulle mutazioni nei geni driver dell’emopoiesi clonale che influenzano i processi responsabili della stenosi, sul tipo di mutazioni coinvolte nel mediare la prognosi sfavorevole e sull’impatto dell’emopoiesi clonale sulla reversibilità della fibrosi cardiaca a seguito della TAVR.
Obiettivo
Degenerative aortic valve stenosis is the most common acquire heart valve disease and will continue to increase as a result of an aging population. There is currently no medical therapy established to halt progression of aortic stenosis and the only definitive treatment is aortic valve replacement either by surgery or transcatheter aortic valve replacement (TAVR). Without valve replacement, the 2 year mortality rate approximates 50 % once patients are symptomatic. Although a number of general risk factors have been described for developing calcified aortic valve disease, risk prediction for progression of CAVD to severe stenosis is still poor. We demonstrated that somatic mutations associated with expansion of hematopoietic cells (“clonal haematopoiesis“ (CH)) are associated with a poor prognosis of patients with aortic valve stenosis undergoing TAVR.
This application aims to address the following major points. We will determine 1) how mutations in the most prevalent CH-driver gene DNMT3A may directly or indirectly affect the pathophysiological processes leading to aortic valve stenosis, and 2) which type of mutation is particularly involved in mediating the poor prognosis. 3) We will determine the impact of CH on the reversibility of cardiac fibrosis after successful replacement of the aortic valve, and 4) determine the relation of CH with senescence and inflammaging. We will use cutting edge single cell and omics technologies to decipher the pathophysiological effects in patient tissues and circulating blood samples and will explore the pathomechanisms induced by DNMT3A CH-driver mutation by assessing cellular communication processes in vitro.
The discovery of relevant of immune system mediated complexities in the progression of aortic valve stenosis and consequent cardiac fibrosis is expected to identify biomarkers and possible novel therapeutic targets to specifically intervene in patients with a high risk for worse outcome.
Campo scientifico
Programma(i)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Argomento(i)
Meccanismo di finanziamento
ERC - Support for frontier research (ERC)Istituzione ospitante
60323 Frankfurt Am Main
Germania