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Cellular and molecular mechanisms of myxomatous mitral valve disease and associated mitral valve...

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Cellular and molecular mechanisms of myxomatous mitral valve disease and associated mitral valve prolapse : the role of Dchs1 and filamin-A

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Cellular and molecular mechanisms of myxomatous mitral valve disease and associated mitral valve prolapse : the role of Dchs1 and filamin-A

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Title	Cellular and molecular mechanisms of myxomatous mitral valve disease and associated mitral valve prolapse : the role of Dchs1 and filamin-A
Author	Sauls, Kimberly Melissa
Date	2015
Affiliation/College	College of Graduate Studies
Department	Regenerative Medicine and Cell Biology
Extent	x, 203 leaves : illustrations; 29 cm
Subject.MeSH	Academic Dissertations Academic Dissertations--South Carolina Mitral Valve Prolapse Filamins
Keywords	Myxomatous Mitral Valve Disease, Filamin-A, Dchs1, Non-Syndromic Mitral Valve Prolapse
Collection	MUSC Theses and Dissertations
Contributing Institution	Waring Historical Library (MUSC)
Rights	Copyright is held by the author.
Language	English
Type	Text
Format	application/pdf
Media Type	Manuscripts
Resource Identifier	mtd2015_sauls_ka
Abstract	Mitral valve prolapse (MVP) affects 1 in 40 people worldwide and is the leading cause of mitral valve surgery. MVP is defined as the displacement of one or both leaflets during ventricular systole and commonly leads to mitral regurgitation as well as other secondary cardiac defects including arrhythmias, congestive heart failure, and sudden cardiac death. Structural changes observed in MVP patients include myxomatous degeneration of the mitral leaflets, which is characterized by collagen fragmentation and accumulation of proteoglycans. Additionally, hyperproliferation and activation of interstitial cells (to myofibroblasts) also contribute to valve enlargement and degeneration, respectively. The molecular and genetic etiology of nonsyndromic MVP is unknown. This is likely due to the lack of knowledge regarding specific genes that cause nonsyndromic MVP in the human population. Work presented here identifies the first genetic mutations in patients with nonsyndromic MVP. Using linkage analysis and deep sequencing, mutations in the cell-‐polarity gene, DCHS1 were identified. These mutations were shown to be loss of function by in vitro assays and zebrafish knockdown. Consistent with this finding, we observe Dchs1 heterozygote mice (Dchs1+/-‐) exhibit structural (myxomatous degeneration), functional (MVP), and molecular (altered Erk1/2 signaling) defects that phenocopy MVP patients. x We traced the etiology of the disease in the Dchs1+/-‐ mice to defects during valve development where valve morphogenetic defects in tissue shape coincident with aberrant myofibroblast differentiation and elevated pErk1/2 activation. We additionally confirm a developmental origin for the disease in another mouse model that conditionally deletes filamin-‐A from valve tissue resulting in myxomatous valvular dystrophy, which leads to MVP. The filamin-‐A mice exhibit developmental defects in valvular cytoskeletal organization and matrix remodeling, which lead to myxomatous mitral leaflets with elevated pErk1/2 activities and increased hematopoietic cell infiltration in the adult. Importantly, defects in both models of disease are observed prior to myxomatous degeneration suggesting processes that control valve shape and maturation are critical for maintaining the valve in a non-‐degenerative state. Thus, we hypothesize that the cell polarity gene Dchs1 regulates adhesion, migration, and alignment of pre-‐valvular fibroblasts, and filamin-‐A regulates matrix remodeling during normal valve morphogenisis. All of which work together to build and shape mitral leaflets during the post-‐EndoMT stage of valve development. As a corollary hypothesis, we propose that infiltration of circulating progenitor cells contribute to disease through the Erk1/2 signaling pathway. The goal of this work is to define molecular and cellular mechanisms by which Dchs1 and filamin-‐A regulate valve morphogenesis and to identify common pathogenic mechanisms of myxomatous degeneration, with the potential benefit of targeting the MEK/Erk pathway and/or immune cell infiltration to abrogate MVP disease pathogenesis.

Cellular and molecular mechanisms of myxomatous mitral valve disease and associated mitral valve prolapse : the role of Dchs1 and filamin-A

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