Date of Award

1-1-2010

Document Type

Campus Access Dissertation

Department

Biomedical Science

First Advisor

Richard L Goodwin

Abstract

Today, congenital heart defects are collectively the most common birth defect as well as the leading cause of birth defect related deaths, which often require surgical procedures, a lifetime of medications and preventative measures on the patient to maintain a working heart and a healthy body. As valvular defects are among the most common and deleterious of all congenital heart defects, it is critical to comprehend cardiac valve development. Extensive studies have made solid progress in delineating the initiation of cardiac valve development. In contrast, little is known about later events of cardiac valve development, during which the soft jelly-like cardiac valve primodia mature into the functional fibrous cardiac valves. The purpose of this study is to investigate embryonic cardiac valve fibrous development and to understand the mechanisms regulating cardiac valve fibrous development. The central hypothesis tested in this study is fluid flow forces play a significant role in regulating fibrous proteins expression and deposition, which are critical components for embryonic cardiac valve morphogenesis.

In chapter 2, our study demonstrated drastic increase of fibrous extracelluar matrix (ECM) proteins mRNA expression during cardiac valve development. Further study on translational level using multiple techniques (trichrome staining, immunofluorescence and TEM) confirmed the post-transcription results, and also showed the distinct spatiotemporal expression patterns of various fibrotic ECM proteins.

In chapter 3, by using the in vitro fluid flow bioreactor culture system, our data suggested fluid flow forces increase fibrous proteins mRNA and protein expression in the atrioventricular (AV) cushion explants. Also, the AV cushion explants exhibited stronger and stiffer material properties compared to the static controls. Further investigation of the mechanotransduction mechanism was carried out by manipulating the RhoA/Rho kinase pathway. From our experiments, RhoA/Rho kinase pathway was shown to bridge the mechanical forces and the biological responses from the AV cushions with increases of fibrous proteins expression and correlated changes of the cushion material properties. In summery, our current study facilitates a better understanding of embryonic cardiac valve development, provides basis for studying pathogenesis of congenital heart valve defects and may shed lights on tissue engineered heart valve design.

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