Pulmonary arterial hypertension (PH), a progressive disease defined by an elevation in the mean pulmonary artery pressure above 25 mm Hg, leads to right heart failure and a significant risk of death. Genetic alterations in two members of the TGF beta superfamily pathways, bone morphogenetic protein receptor II (BMPR II) and the TGF-beta receptor I, ALK1, have been implicated in the pathogenesis of PH. Despite the genetic and functional significance of the TGF pathway, it is unclear how dysregulation of TGF signaling results in PAH. We hypothesize that the development of PAH results from an imbalance in TGF signaling within endothelial cells. Specifically, enhanced TGF signaling in endothelial cells promotes a phenotypic change that allows the cells to undergo endothelial-mesenchymal transition and contribute to the smooth muscle or myofibroblast cell population. This project addresses one of the fundamental questions in pulmonary hypertension, the mechanism by which altered TGF beta signaling contributes to the pathogenesis of PH. The complexity of this question is amplified by the myriad of cellular processes in which TGF beta participates and the multiple cell types (endothelial, smooth muscle, and adventitial fibroblasts) it is capable of affecting and which may influence the development of pulmonary hypertension. In order to begin addressing the molecular pathway, this project proposes to study the role of TGF beta signaling in endothelial cells. We will rely on an endothelial cell inducible deletion of TGF beta receptor II and the well-established hypoxic model of PH to demonstrate the role of endothelial cell TGF beta signaling in the development of PH. Endothelial-mesenchymal transition will be characterized by genetically tagging endothelial cells and following their fate after exposure to chronic hypoxia. Finally, we will demonstrate that TGF beta signaling is required for endothelial-mesenchymal transition and test a novel inhibitor of TGF beta mediated transition. Understanding the molecular mechanism by which this occurs can provide insight into the initiation of human PAH and the development of novel therapeutic targets.

Public Health Relevance

Pulmonary arterial hypertension (PAH) is a progressive disease with limited therapies defined as an elevation in the mean pulmonary artery pressure which may lead to right heart failure and death. The Transforming Growth Factor beta superfamily has been implicated in the disease, but the molecular mechanism by which alterations in this gene family result in the disease is unknown. Understanding the mechanism of the disease will provide the opportunity for developing new screening tests and therapeutic interventions.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21HL096982-02
Application #
8197835
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Eu, Jerry Pc
Project Start
2011-01-01
Project End
2013-12-31
Budget Start
2012-01-01
Budget End
2013-12-31
Support Year
2
Fiscal Year
2012
Total Cost
$246,000
Indirect Cost
$96,000
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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