Biomechanical and Molecular Approaches to Aortic Valve Disease in a Mouse Model

<p>Aortic valve disease (AVD) occurs in 2.5% of the human population and is a significant cause of cardiovascular mortality. Aortic valve malformation is a heritable condition that underlies the majority of cases, suggesting a developmental origin. Increased interstitial cell activation and abnormal extracellular matrix (ECM) remodeling are hallmark features of AVD. Elastin is one of the primary ECM proteins in the aortic valve and is responsible for valve extension and recoil. Mutations or deletions in the elastin gene cause elastin haploinsufficiency, a clinical condition associated with valve abnormalities in 20-45% of the patients. However, the site and temporal onset of disease, together with progressive alterations in biomechanical and molecular properties of the regional aortic valve are poorly understood. </p><p>Our long-term goal is to leverage the mechanical and mechanistic underpinnings of AVD to develop durable tissue engineered substitutes for use in surgeries. The objective of this dissertation study is to investigate the Young’s elastic modulus and cell-ECM phenotype in aortic valve (cusp and annulus regions) tissue, using the elastin haploinsufficient (Eln+/-) mouse. Studies from our lab have established this mouse as a model of aortic valve malformation with latent AVD. The central hypothesis of the proposed research is that elastin haploinsufficiency in aortic valve tissue causes increased valve interstitial cell (VIC) activation leading to maladaptive ECM remodeling, progressive biomechanical alterations, and ultimately AVD. The strength of this dissertation is in the combination of engineering and developmental approaches to elucidate progressive pathogenesis of human AVD in a mouse model. Overall, these studies provide information necessary for future translational research efforts such as the development of tissue bioprostheses and novel therapeutics.</p>

Name thesis:degree_name

PhD

Level thesis:degree_level

doctoral

Discipline thesis:degree_discipline

Engineering and Applied Science: Biomedical Engineering

Grantor dc:publisher

University of Cincinnati

Year dc:date

2012

Author dc:creator

• Krishnamurthy, Varun K.

Contributors dc:contributor

• Hinton, Robert

• Biomedical Research
• elastin haploinsufficiency
• aortic valve
• aorta
• micropipette aspiration
• matrix remodeling

Statement dc:rights

• unrestricted
• This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.

Language dc:language

English

Repository record dc:identifier

http://rave.ohiolink.edu/etdc/view?acc_num=ucin1354297165

OAI identifier oai:identifier

oai:etd.ohiolink.edu:ucin1354297165