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Myocardial afterload regulates atrioventricular valve development in zebrafish

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dc.contributor.authorAhuja, Neha, author
dc.contributor.authorGarrity, Deborah, advisor
dc.contributor.authorSloan, Daniel, committee member
dc.contributor.authorMykles, Don, committee member
dc.contributor.authorTjalkens, Ron, committee member
dc.date.accessioned2020-08-31T10:12:03Z
dc.date.available2021-08-24T10:12:03Z
dc.date.issued2020
dc.description.abstractThe incidence of congenital heart disease (CHD) is estimated to be 1% of all human births. CHD of the heart valves occurs in over 50% of CHD cases. Despite significant clinical interest, the molecular mechanisms that govern valve development remain poorly elucidated. As the heart develops, blood flow and blood pressure increase rapidly to support the growing demands of the embryo. Our group has previously shown that pressure at the developing atrioventricular valve dramatically increases through development. Consequently, we hypothesized that afterload—defined as the pressure the ventricle must overcome in order to pump blood through the body—may be a cue that cardiac valve cells read and respond to build a valve leaflet. Here, we present a zebrafish model in which afterload has been increased through the use of vasopressin, a vasoconstrictive drug. We first show that application of vasopressin reliably produces an increase in afterload without directly acting on cardiac tissue in zebrafish embryos. To evaluate cardiac function and valve leaflet dynamics, we took a quantitative live-imaging approach. Consistent with pathology seen in adult human patients with clinically high afterload, we see defects in both form and function of the valve leaflets. To identify the cause of this functional defect, we utilized in situ hybridization to evaluate makers of cell differentiation for both valve leaflet cells and the adjacent myocardial cells. Our results suggest that this valve defect is due to changes in atrioventricular myocyte differentiation and signaling, rather than pressure directly acting on the valve leaflet cells. We next took a transcriptomics approach to identify regulators of atrioventricular myocyte differentiation and identified a subset of differentially expressed transcription factors that are putatively responsible for sensing afterload. Together, our results show that afterload regulates the physiological and molecular state of the developing valve.
dc.format.mediumborn digital
dc.format.mediumdoctoral dissertations
dc.identifierAhuja_colostate_0053A_16193.pdf
dc.identifier.urihttps://hdl.handle.net/10217/211807
dc.languageEnglish
dc.language.isoeng
dc.publisherColorado State University. Libraries
dc.relation.ispartof2020-
dc.rightsCopyright and other restrictions may apply. User is responsible for compliance with all applicable laws. For information about copyright law, please see https://libguides.colostate.edu/copyright.
dc.subjectdevelopmental biology
dc.subjectvalve
dc.subjectbiomechanics
dc.subjectzebrafish
dc.subjectheart
dc.titleMyocardial afterload regulates atrioventricular valve development in zebrafish
dc.typeText
dcterms.embargo.expires2021-08-24
dcterms.embargo.terms2021-08-24
dcterms.rights.dplaThis Item is protected by copyright and/or related rights (https://rightsstatements.org/vocab/InC/1.0/). You are free to use this Item in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you need to obtain permission from the rights-holder(s).
thesis.degree.disciplineCell and Molecular Biology
thesis.degree.grantorColorado State University
thesis.degree.levelDoctoral
thesis.degree.nameDoctor of Philosophy (Ph.D.)

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