A joint project of the Graduate School, Peabody College, and the Jean & Alexander Heard Library

Title page for ETD etd-03192015-155246

Type of Document Dissertation
Author Chen, Joseph
Author's Email Address joseph.chen@vanderbilt.edu
URN etd-03192015-155246
Title The Mechanobiology of Notch1 Deficiency in Calcific Aortic Valve Disease
Degree PhD
Department Biomedical Engineering
Advisory Committee
Advisor Name Title
W. David Merryman Committee Chair
Christopher B. Brown Committee Member
H. Scott Baldwin Committee Member
Hak-Joon Sung Committee Member
Michael I. Miga Committee Member
  • aortic valve
  • valvular disease
  • mechanobiology
Date of Defense 2015-03-12
Availability unrestricted
Calcific aortic valve disease (CAVD) is the predominant valvular disease in the developed world, affecting over five million individuals in the United States alone and manifests itself as a progressive disease resulting in the obstruction of left ventricular outflow, decreased cardiac output, and eventual heart failure. Presently, treatment for CAVD is limited to surgical aortic valve replacement, a high risk procedure especially for the population affected, and although significant advances have been made to reduce the associated risk with this procedure, a non-surgical treatment option is preferred. Unfortunately, current efforts to develop pharmacological treatments have been largely unsuccessful at preventing or slowing down the progression of CAVD; this lack of efficacy can be attributed to the incomplete understanding of the etiology of CAVD. Thus, focused attention must be placed on elucidating the underlying mechanisms of CAVD initiation and evolution in order to develop novel and effective pharmacological drugs. At the tissue level, normal supple leaflets are transformed into thickened, stiff, and calcified leaflets; these striking changes are attributed to the aberrant behavior of the resident cell population, the aortic valve interstitial cells (AVICs), which are believed to play significant roles in leaflet thickening and calcification. Investigating what factors contribute to AVIC differentiation into pathological phenotypes and further how they generate valvular calcification is essential to the understanding of CAVD etiology. It has been demonstrated that CAVD development is tightly regulated by biomolecular, mechanobiological, and genetic factors. Previous studies have focused on describing the effect of biomolecular cues on CN development; however, many mechanobiological and genetic factors that have significant in vivo relevance have not been thoroughly assessed. In an effort to gather insight towards CAVD processes in vivo, we believe that investigations into the role of mechanical strain and the effect of Notch1 mutation on AVIC biology and calcification would provide novel insights towards CAVD etiology that can contribute to the development of effect therapeutics.
  Filename       Size       Approximate Download Time (Hours:Minutes:Seconds) 
 28.8 Modem   56K Modem   ISDN (64 Kb)   ISDN (128 Kb)   Higher-speed Access 
  Chen.pdf 13.65 Mb 01:03:10 00:32:29 00:28:25 00:14:12 00:01:12

Browse All Available ETDs by ( Author | Department )

If you have more questions or technical problems, please Contact LITS.