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Title page for ETD etd-07062015-155323


Type of Document Dissertation
Author Prewitt, Allison Renee
URN etd-07062015-155323
Title Src Kinase Activation in Pulmonary Arterial Hypertension
Degree PhD
Department Cell and Developmental Biology
Advisory Committee
Advisor Name Title
Ethan Lee Committee Chair
Anne Kenworthy Committee Member
David Harrison Committee Member
Mark de Caestecker Committee Member
Matthew Tyska Committee Member
Keywords
  • BMPR2
  • Endothelial Dysfunction
  • Src kinase
  • Caveolae
  • Caveolin-1
  • Pulmonary Hypertension
Date of Defense 2015-07-02
Availability unrestricted
Abstract
Heritable Pulmonary Arterial Hypertension (HPAH) is a rare, fatal disease of the pulmonary vasculature for which there is no cure. The majority of HPAH patients inherit mutations in the BMP type 2-receptor gene, BMPR2, but how these promote pulmonary vascular disease is unclear. In this work, we show BMPR2 mutations promote Src-kinase activation pulmonary endothelial cells (PECs) isolated from Bmpr2 mutant mice. We show increased Src activation leads to endothelial barrier defects due in part to enhanced Src-mediated caveolar endocytosis and that these defects can be rescued using Src kinase inhibitors. We go on to show that pulmonary endothelial cells and late outgrowth endothelial progenitor cells isolated from idiopathic PAH patients show similar increases in Src kinase activation suggesting that Src kinase activation may be a common disease mechanism in PAH. Therefor, these studies provide evidence for the use of Src kinase inhibitors in the treatment of pulmonary arterial hypertension.
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