Advisor

Warnock, James N.

Committee Member

McCarthy, Fiona

Committee Member

Liao, Jun

Committee Member

Burgess, Shame

Committee Member

Elder, Steven

Date of Degree

1-1-2009

Document Type

Dissertation - Open Access

Major

Biomedical Engineering

Degree Name

Doctor of Philosophy

College

James Worth Bagley College of Engineering

Department

Department of Agricultural and Biological Engineering

Abstract

Calcific aortic valve disease (CAVD) is the most common cause of aortic valve failure and replacement in the elderly population, affecting 25% of the population over 65 years of age. Current pharmacological approaches for preventing the onset and progression of calcific aortic valve disease have not shown consistent benefits in clinical studies. Differentiation of valvular interstitial cells (VICs) into osteoblast–like cells is an integral step in the calcification process. Although clinical evidence suggests hypertension as a potential candidate contributing to the development of CAVD, the underlying molecular mechanisms that cause de-differentiation remain unclear. The present study investigates the role of elevated cyclic pressure in modulating osteoblast differentiation pathways in VICs in vitro. We used a combination of systems biology modeling and pathway-based analyses to identify novel genes and molecular mechanisms that are activated in valve tissue during exposure to elevated pressure conditions. Our results show that elevated pressure induces a gene expression pattern in valve tissue that is considerably similar to that seen in CAVD, underlining the key role of hypertension as an initiating factor in the onset of pathogenesis. In addition, our analysis revealed a set of genes that was not previously known to be regulated in valve tissue in a pressure dependent manner. Currently, the molecular mechanisms involved in CAVD and their associations with changes in local mechanical environment are poorly understood, and thus a better understanding of the cell based process mediating CAVD progression will improve our ability to develop potential medical therapies for this disease.

URI

https://hdl.handle.net/11668/17494

Comments

OPN||RUNX2||Angiotensin II||ALP||Cyclic Pressure||Valvular Interstitial Cells||BMP-7||SMAD1

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