{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T02:04:48Z","timestamp":1789524288191,"version":"build-2803163510"},"reference-count":54,"publisher":"American Society for Clinical Investigation","issue":"14","license":[{"start":{"date-parts":[[2025,7,15]],"date-time":"2025-07-15T00:00:00Z","timestamp":1752537600000},"content-version":"vor","delay-in-days":56,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["GM150838"],"award-info":[{"award-number":["GM150838"]}]},{"name":"NIH","award":["HL173271"],"award-info":[{"award-number":["HL173271"]}]},{"name":"NIH","award":["HL131872"],"award-info":[{"award-number":["HL131872"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,7,15]]},"abstract":"<jats:p>\n                    Mitral valve prolapse is often benign, but progression to mitral regurgitation may require invasive intervention and there is no specific medical therapy. An association of mitral valve prolapse with Marfan syndrome resulting from pathogenic\n                    <jats:italic>FBN1<\/jats:italic>\n                    variants supports the use of hypomorphic fibrillin-1 mgR mice to investigate mechanisms and therapy for mitral valve disease. mgR mice developed severe myxomatous mitral valve degeneration with mitral regurgitation by 12 weeks of age. Persistent activation of TGF-\u03b2 and mTOR signaling along with macrophage recruitment preceded histological changes at 4 weeks of age. Short-term mTOR inhibition with rapamycin from 4 to 5 weeks of age prevented TGF-\u03b2 overactivity and leukocytic infiltrates, while long-term inhibition of mTOR or TGF-\u03b2 signaling from 4 to 12 weeks of age rescued mitral valve leaflet degeneration. Transcriptomic analysis identified integrins as key receptors in signaling interactions, and serologic neutralization of integrin signaling or a chimeric integrin receptor altering signaling prevented mTOR activation. We confirmed increased mTOR signaling and a conserved transcriptome signature in human specimens of sporadic mitral valve prolapse. Thus, mTOR activation from abnormal integrin-dependent cell\u2013matrix interactions drives TGF-\u03b2 overactivity and myxomatous mitral valve degeneration, and mTOR inhibition may prevent disease progression of mitral valve prolapse.\n                  <\/jats:p>","DOI":"10.1172\/jci183558","type":"journal-article","created":{"date-parts":[[2025,5,20]],"date-time":"2025-05-20T12:00:24Z","timestamp":1747742424000},"source":"Crossref","is-referenced-by-count":11,"title":["Integrin-mediated mTOR signaling drives TGF-\u03b2 overactivity and myxomatous mitral valve degeneration in hypomorphic fibrillin-1 mice"],"prefix":"10.1172","volume":"135","author":[{"given":"Fu","family":"Gao","sequence":"first","affiliation":[{"name":"Division of Cardiac Surgery, Department of Surgery, Yale School of Medicine, New Haven, Connecticut, USA."},{"name":"Department of Biomedical Engineering, Yale University, New Haven, Connecticut, USA."},{"name":"Department of Pathology, Yale School of Medicine, New 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