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Title page for ETD etd-03242009-105847


Type of Document Dissertation
Author Pyle, Amy Lauren
URN etd-03242009-105847
Title SPRR3 Regulation and Function in the Atherosclerotic Microenvironment
Degree PhD
Department Pathology
Advisory Committee
Advisor Name Title
Jeffery M. Davidson Committee Chair
Jeff Reese Committee Member
Jin Chen Committee Member
Richard L. Hoover Committee Member
Samuel A. Santoro Committee Member
Keywords
  • biomechanical stress
  • atherosclerosis
  • Vascular smooth muscle cells
  • SPRR3
  • Blood-vessels -- Mechanical properties
  • Atherosclerosis -- Molecular aspects
Date of Defense 2009-02-10
Availability unrestricted
Abstract
Atherosclerosis is a chronic vascular disease which is the underlying cause of over half the deaths in the United States each year. Variations in local vascular hemodynamics predispose select sites in the vasculature to atherosclerosis and the atherosclerotic lesions, in turn, alter the biomechanical functioning of the local microenvironment, the consequences of which are not well understood on a molecular level. Work from our lab demonstrated that the small proline rich repeat protein 3 (SPRR3), which is known to be biomechanically responsive in stratified epithelia, is selectively expressed in vascular smooth muscle cells (VSMCs) in the atherosclerotic microenvironment. SPRR3 has stable head and tail domains that contain amino acid domains which are substrates for transglutaminase. Additionally, SPRR3 has a highly flexible, proline-rich central domain that is believed to confer elasticity. We have shown that in VSMCs, SPRR3 transcripts are upregulated by prolonged cyclic strain, as sensed through integrin α1β1 integrin binding to type I collagen. Furthermore, we have shown that SPRR3 overexpression in VSMCs promotes migration and inhibits contraction, though this effect is independent of transglutamination of the protein. Ongoing and future work will demonstrate a role for SPRR3 in signaling pathways, such as in the Akt pathway. Ultimately, the study of SPRR3 will provide insight into the molecular pathogenesis of atherosclerosis.
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