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dc.contributor.advisorSchwartz, David A.
dc.contributor.authorHancock, Laura
dc.contributor.committeememberTaylor, Matthew
dc.contributor.committeememberNiswander, Lee
dc.contributor.committeememberGutierrez-Hartmann, Arthur
dc.contributor.committeememberEvans, Christopher
dc.date.accessioned2017-06-13T18:25:05Z
dc.date.available2017-11-26T08:20:26Z
dc.date.submitted2017
dc.descriptionIncludes bibliographical references.
dc.descriptionSpring
dc.description.abstractIdiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with a median survival following diagnosis of two to three years and no known curative therapy. A common gain-of-function variant in the promoter of the lung gel-forming mucin gene MUC5B (rs35705950) is the strongest risk factor for the development of IPF, a finding confirmed by 10 independent studies. Based on this observation, I hypothesize that excess expression of MUC5B damages the distal lung, and when combined with an exogenous insult, results in increased fibroproliferation. This project uses three transgenic strains of mice on a C57BL/6 background. One strain overexpresses MUC5B in the conducting airway epithelia (Scgb1a1 Tg), one strain overexpresses MUC5B in type 2 alveolar epithelia (SPC Tg), and one strain is deficient in MUC5B (Muc5b-/-). Mice were dosed intratracheally with bleomycin three times over seven weeks, then lung tissues were collected for assessment of collagen deposition, tissue remodeling, and gene expression. To examine the effect of pharmacologically enhanced mucociliary clearance following bleomycin treatment, SPC Tg+ animals were dosed with a mucolytic compound via inhalation. More lung collagen deposited in bleomycin exposed Scgb1a1 Tg+ and SPC Tg+ Muc5b overexpressing mice compared to wild type littermates. Accordingly, Muc5b-/- mice exhibited less lung collagen than their wild type littermates, demonstrating a direct relationship between Muc5b expression and fibrosis. Quantitative PCR and tissue staining of Scgb1a1 Tg+ lungs showed an increase in endoplasmic reticulum (ER) stress gene expression and cell apoptosis in Muc5b overexpressing animals compared to controls. SPC Tg+ overexpressing mice possessed a thicker luminal mucus layer and displayed significantly slower mucociliary transport velocity, prompting investigation of mucolytic compounds. Mucolytic drugs with variable durations of action effectively reduced polymeric mucus into dimers and monomers and they simultaneously induced the clearance of inflammatory cells from the lung. Following bleomycin exposure, SPC Tg+ animals treated with a long-acting mucolytic experienced improved survival and decreased collagen deposition. These results indicate that excess MUC5B promotes lung fibrosis following injury with bleomycin, and the absence of MUC5B appears to be protective. Increased clearance of MUC5B through mucolytic inhalation also reduces fibrotic changes, suggesting a potential future therapeutic intervention for IPF.
dc.identifierHancock_ucdenveramc_1639D_10402.pdf
dc.identifier.urihttp://hdl.handle.net/10968/1922
dc.languageEnglish
dc.publisherUniversity of Colorado Anschutz Medical Campus. Strauss Health Sciences Library
dc.rightsCopyright of the original work is retained by the author.
dc.rights.accessEmbargo Expires: 11/26/2017
dc.subjectMouse lung physiology
dc.subjectMucolysis
dc.subject.meshEndoplasmic Reticulum Stress
dc.subject.meshIdiopathic Pulmonary Fibrosis
dc.subject.meshBleomycin
dc.subject.meshMucin-5B
dc.subject.meshMice
dc.titleGenetic or pharmacologic modulation of MUC5B influences the development of pulmonary fibrosis in mice
dc.typeText
dcterms.embargo.expires2017-11-26
thesis.degree.disciplineHuman Medical Genetics & Genomics
thesis.degree.grantorUniversity of Colorado at Denver, Anschutz Medical Campus
thesis.degree.levelDoctoral
thesis.degree.nameDoctor of Philosophy (Ph.D.)


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