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dc.contributor.authorLui, Wendy
dc.identifier.citationSource: Dissertation Abstracts International, Volume: 78-01(E), Section: B.;Advisors: Bin Zhou.
dc.description.abstractNuclear factor of activated T cells, cytoplasmic 1 (Nfatc1) is a transcription factor that is expressed specifically in the endocardium during heart development. Nfatc1 has been shown to inhibit epithelial to mesenchymal transition (EMT) and maintain valve endocardial progenitors. Aberrations in Nfatc1 signaling results in defective or missing semilunar valves and suggests its role in remodeling endocardial cushions into valve leaflets -- however, the molecular pathways by which Nfatc1 regulates this process are unknown. Furthermore, there exists two isoforms of Nfatc1 in the heart; Nfatc1a and Nfatc1b, but isoform specific functions have not been characterized. In this Thesis, I have determined that Nfatc1a plays a critical temporal role in valve remodeling by suppressing proliferation of valve mesenchymal cells through upregulation of Hbegf. Recently, Nfatc1 expressing endocardial cells have been identified as the major progenitor population for coronary artery (CA) endothelium. To elucidate the functions of Nfatc1 in CA development, I impaired expression of Nfatc1a from the endocardium prior to the formation of CAs and identified vascular defects affecting vascular patterning and increased ventricular vascular density. Gene expression analysis indicates that loss of Nfatc1a results in the upregulation of key angiogenesis regulating genes, Dll4 and Notch. Additionally, Nfatc1 directly binds to the Dll4 promoter to suppress its activity. Altogether, these results indicate that Nfatc1 regulates CA development by modulating the expression of Dll4, and Nfatc1a , specifically, is indispensable for proper CA formation. Unexpectedly, in mouse hearts following surgically induced myocardial infarction (MI), I found Nfatc1 expression in the endothelium of CA within the infarcted tissue during the healing phase after MI. Once a stable scar had formed, Nfatc1 expression was no longer observed. Nfatc1 is normally not expressed in the mouse heart postnatally nor been found to be expressed within CA endothelium during development. This finding suggests an interesting research direction in evaluating Nfatc1 as a target for post-infarction cardiac repair. Altogether, the findings of this Thesis project have uncovered the mechanisms by which Nfatc1 regulates valve remodeling, discovered a novel regulatory role for Nfatc1 during CA development, and uncovered Nfatc1 as a potential therapeutic target for the treatment of CAD.
dc.publisherProQuest Dissertations & Theses
dc.subjectDevelopmental biology.
dc.titleCharacterization of Nfatcl in the development of cardiac valves and coronary arteries

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