Roles of MicroRNAs in Fetal Lung Development

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dc.contributor.advisorLiu, Qinghuaen
dc.contributor.committeeMemberMendelson, Carole R.en
dc.contributor.committeeMemberMinna, John D.en
dc.contributor.committeeMemberMendell, Joshua T.en
dc.creatorGuo, Weien
dc.creator.orcid0000-0002-0239-3122
dc.date.accessioned2018-08-24T20:37:41Z
dc.date.available2018-08-24T20:37:41Z
dc.date.created2016-08
dc.date.issued2016-05-27
dc.date.submittedAugust 2016
dc.date.updated2018-08-24T20:31:33Z
dc.description.abstractLung alveolar type II cells uniquely synthesize surfactant, a developmentally-regulated lipoprotein that is essential for breathing. Expression of the major surfactant protein, SP-A, in midgestation human fetal lung (HFL) is dramatically induced by cAMP. cAMP induction of SP-A expression is repressed by TGF-β and by hypoxia. In this study, we found that expression of the miR-29 family was significantly upregulated in epithelial cells isolated from mouse fetal lung during late gestation and in epithelial cells isolated from HFL explants during type II cell differentiation in culture. MiR-29 expression in cultured HFL epithelial cells was increased by cAMP and inhibited by hypoxia, whereas the miR-29 target, TGF-β2, was coordinately oppositely regulated. Knockdown of the miR-29 family in cultured HFL type II cells blocked cAMP-induced SP-A expression and accumulation of surfactant-containing lamellar bodies, suggesting its physiological relevance. This occurred through derepression of TGF-β signaling. Notably, cAMP increased binding of endogenous thyroid transcription factor-1 (TTF-1/Nkx2.1) to the miR-29ab1 promoter in HFL type II cells and TTF-1 increased miR-29ab1 promoter-driven luciferase activity in co-transfection assays. Together, these findings identify miR-29 family members as TTF-1-driven mediators of SP-A expression and type II cell differentiation through repression of TGF-β signaling.en
dc.format.mimetypeapplication/pdfen
dc.identifier.oclc1049807487
dc.identifier.urihttps://hdl.handle.net/2152.5/5729
dc.language.isoenen
dc.subjectAlveolar Epithelial Cellsen
dc.subjectLungen
dc.subjectMicroRNAsen
dc.subjectNuclear Proteinsen
dc.subjectTranscription Factorsen
dc.titleRoles of MicroRNAs in Fetal Lung Developmenten
dc.typeThesisen
dc.type.materialtexten
thesis.degree.departmentGraduate School of Biomedical Sciencesen
thesis.degree.disciplineBiological Chemistryen
thesis.degree.grantorUT Southwestern Medical Centeren
thesis.degree.levelDoctoralen
thesis.degree.nameDoctor of Philosophyen

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