Page 1 |
Save page Remove page | Previous | 1 of 211 | Next |
|
small (250x250 max)
medium (500x500 max)
large ( > 500x500)
Full Resolution
All (PDF)
|
This page
All
Subset |
SIGNALING PATHWAYS IN CARDIOVASCULAR DEVELOPMENT
by
Peng Li
A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(NEUROSCIENCE)
August 2011
Copyright 2011 Peng Li
Object Description
| Title | Signaling pathways in cardiovascular development |
| Author | Li, Peng |
| Author email | pengli@usc.edu;rockly05@yahoo.com |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Neuroscience |
| School | College of Letters, Arts And Sciences |
| Date defended/completed | 2011-06-02 |
| Date submitted | 2011-08-08 |
| Date approved | 2011-08-09 |
| Restricted until | 2011-08-09 |
| Date published | 2011-08-09 |
| Advisor (committee chair) |
Sucov, Henry M. Chen, Jeannie |
| Advisor (committee member) |
Lu, Wange Maxson, Robert |
| Abstract | Congenital cardiovascular disease is the number one birth defect causing deaths in the first year of life in children. The embryonic development of the heart involves various signaling pathways and multiple cell lineages, the interactions of which are critical for normal heart morphogenesis and function. Understanding these gene regulations and cell-cell interactions will provide insights for the molecular and cellular mechanisms underlying both cardiogenesis and cardiovascular disorders. In this thesis, we utilized the genetic modified mouse models to study the congenital cardiovascular diseases. ❧ Around one-third of congenital heart defects involve compromised outflow tract formation. Defects in the differentiation of the second heart field (SHF) result in shortened and misaligned outflow vessels, whereas defects in outflow tract septation result in a persisting single vessel. In this study, I found that as the initial SHF population differentiates and then incorporates into the outflow tract, it is replenished from a surrounding progenitor territory. This latter phase of SHF progenitor differentiation is dependent on retinoic acid (RA) signaling, which results in a shortened and misaligned outflow tract in mutant mice. In addition, as a consequence of this primary defect, the outflow tract of RA receptor mutant embryos becomes misspecified along its proximal-distal axis, as evidenced by ectopic expression of TGFβ2 and ectopic mesenchymal transformation of the endocardium. The reduction of TGFβ2 gene dosage in the RA receptor mutant background restores septation but does not rescue alignment defects, suggesting that ectopic TGFβ2 may cause excess or ectopic mesenchymal transformation of the endocardium that disrupts OFT organization and thereby results in septation failure. This work uncouples SHF differentiation from the later and indirect consequence on outflow tract septation. ❧ The outflow tract connects to systemic and pulmonary circulation through pharyngeal arch artery derived great vessels, the formation of which is a critical early step in the process that leads to the mature cardiovascular organization. We demonstrated here that the pharyngeal arch artery formation in mouse embryos is initiated by vasculogenesis, and in this process RA receptors in mesoderm cells autonomously control the coalescence of the angioblasts into nascent blood vessels. ❧ Ventricular chamber defects account for another large group of congenital heart diseases. Epicardium, the outmost layer of the heart, has been implicated as the source for mitogenic factors promoting the cardiomyocyte proliferation, although the specific factors involved have not been identified adequately. We found that during midgestation heart development, the embryonic epicardium expresses Igf2, the absence of which results in ventricular wall hypoplasia. Similarly, conditional disruption of the two IGF receptors genes Igf1r and Insr together in heart myocardium caused decreased myocardium proliferation. These results define IGF2 as a previously unexplored factor that is required for normal ventricular chamber development. |
| Keyword | heart; IGF; mouse; outflow tract; pharyngeal arch artery; retinoic acid |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Provenance | Electronically uploaded by the author |
| Type | texts |
| Legacy record ID | usctheses-m |
| Rights | Li, Peng |
| Access conditions | The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the author, as the original true and official version of the work, but does not grant the reader permission to use the work if the desired use is covered by copyright. It is the author, as rights holder, who must provide use permission if such use is covered by copyright. The original signature page accompanying the original submission of the work to the USC Libraries is retained by the USC Libraries and a copy of it may be obtained by authorized requesters contacting the repository e-mail address given. |
| Repository name | University of Southern California Digital Library |
| Repository address | USC Digital Library, University of Southern California, University Park Campus MC 7002, 106 University Village, Los Angeles, California 90089-7002, USA |
| Repository email | cisadmin@usc.edu |
| Archival file | uscthesesreloadpub_Volume71/etd-LiPeng-260.pdf |
Description
| Title | Page 1 |
| Full text | SIGNALING PATHWAYS IN CARDIOVASCULAR DEVELOPMENT by Peng Li A Dissertation Presented to the FACULTY OF THE USC GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (NEUROSCIENCE) August 2011 Copyright 2011 Peng Li |
Comments
Post a Comment for Page 1
