We have developed a novel concept that emphysema occurs due to a failure of the cellular and molecular lung maintenance (survival) program, since simultaneous blockade of Vascular Endothelial Growth Factor Receptors (VEGF-R) leads to apoptotic destruction of the lung parenchyma, by means of the mutual interaction of lung oxidative stress and apoptosis. Both VEGF-R1 and VEGF-R2 may contribute to survival of lung endothelial cells and may have novel roles in maintaining lung structural integrity and lung homeostasis. We hypothesize that both VEGF-R1 and VEGF-R2 promote alveolar endothelial cell survival and contribute to the maintenance of alveolar structure and that blockade of both VEGF-R1 and VEGF-R2 is required to cause endothelial cell apoptosis and emphysema. Endothelial cell apoptosis triggers a feedback interaction with further alveolar cell (epithelial cells and septal fibroblasts) apoptosis, septal oxidative stress and alveolar proteolysis, ultimately resulting in septal destruction. The extent of endothelial cell apoptosis determines the severity and reversibility of emphysema. In this renewal, we will: 1. Determine the mechanisms by which the blockade of VEGF-R1 or VEGF-R2 disrupts lung maintenance and causes emphysema (Specific Aim 1); 2. Determine whether the extent and kinetics of VEGF receptor-independent alveolar endothelial cell death with a lung homing and cell killing chimeric peptide directs the degree of severity and reversibility of emphysematous lung destruction (Specific Aim 2); and, 3. Uncover septal cellular and molecular events downstream of or simultaneous to endothelial cell apoptosis that mediate alveolar septal destruction (Specific Aim 3). We will perform in vivo studies in mice and investigate real time lung alveolar responses in isolated lung preparations, with a comprehensive set of structural and functional endpoints of apoptosis, oxidative stress, and matrix protease activation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL066554-10
Application #
7661748
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Croxton, Thomas
Project Start
2000-09-29
Project End
2010-07-31
Budget Start
2008-08-12
Budget End
2010-07-31
Support Year
10
Fiscal Year
2007
Total Cost
$237,345
Indirect Cost
Name
University of Colorado Denver
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
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