Homeobox genes encode transcription factors that control tissue patterning and morphogenesis, yet their role in pulmonary vascular development remains obscure. Our preliminary studies indicate that the paired related homeobox gene, Prxl, is required for lung vascularization via its ability to promote both endothelial cell (EC) differentiation and vascular network formation.
The Specific Aims of this proposal are as follows: (1) To define how Prxl drives EC differentiation during lung vasculogenesis: Tie-GFP transgenic mice will be used to locate Prxl-expressing ECs throughout lung development, and chromatin immunoprecipitation assays will be used to identify direct targets for Prxl in differentiating lung ECs. The validity and functions of Prxl and its targets will be evaluated using Prxl-null mice and tissue culture models of pulmonary EC differentiation; (2) To determine how Prxl-dependent induction of the extracellular matrix protein tenascin- C (TN-C) promotes lung vascular network formation: Knockout studies using fetal lung explants, yeast 2- hybrid assays and tissue recombinations will be used to understand how TN-C promotes Prxl-dependent network formation; (3) To delineate how focal adhesion kinase (FAK) controls Prxl during vascular network formation: Adenoviral-based inhibition of FAK activity, and dissection of the Prxl gene promoter will be used to comprehend how FAK controls Prxl transcription and vascular morphogenesis in the lung. Overall, this proposal will result in a detailed understanding of the role of Prxl throughout fetal lung vascularization. This study should provide new concepts in lung vascular biology, and will hopefully result in novel diagnostic tools and therapies for the treatment of newborn and adult diseases in which the pulmonary vasculature is compromised, eg. bronchopulmonary dysplasia and pulmonary hypertension.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL079196-04
Application #
7421006
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Blaisdell, Carol J
Project Start
2005-07-15
Project End
2010-05-31
Budget Start
2008-06-01
Budget End
2010-05-31
Support Year
4
Fiscal Year
2008
Total Cost
$373,346
Indirect Cost
Name
University of Pennsylvania
Department
Pathology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Cohen, Ethan David; Ihida-Stansbury, Kaori; Lu, Min Min et al. (2009) Wnt signaling regulates smooth muscle precursor development in the mouse lung via a tenascin C/PDGFR pathway. J Clin Invest 119:2538-49
Jones, Peter Lloyd (2007) Move on!: smooth muscle cell motility paired down. Circ Res 100:757-60