Recovery of endothelial integrity after lung vascular injury is a poorly understood aspect of vascular homeostasis. Our long term goals using molecular, cellular, and in vivo approaches are to elucidate mechanisms of endothelial barrier repair following vascular injury and identify novel therapeutic targets to prevent persistent lung vascular injury and leaky microvessels associated with sepsis-induced acute lung injury. FoxM1 is a member of the Forkhead box (Fox) family of transcription factors essential for cell proliferation. FoxM1-null mutation in mice causes embryonic lethality due to improper execution of mitosis and the resulting polyploid cells in heart and liver. We will test the general HYPOTHESIS that FoxM1 is a critical determinant of endothelial repair following lung vascular injury. Our objective is to determine the essential role of FoxM1 in regulating endothelial cell proliferation and re-annealing endothelial junctions, thereby restoring endothelial integrity following lung vascular injury. The studies will address the following Specific Aims: 1. To determine the mechanisms of regulation of FoxM1 expression in response to lung vascular injury. We will dissect the signaling pathways that mediate FoxM1 induction in the pulmonary microvasculature following LPS-induced lung vascular injury. We will test the hypothesis that loss of endothelial cell-cell contact following lung vascular injury induces FoxM1 expression in endothelial cells through PI3K/Akt-dependent downregulation of p27Kip1, a key determinant of cell contact inhibition. 2. To elucidate the molecular mechanisms of FoxM1-regulated endothelial cell proliferation. We will characterize the defects in cell cycle progression of FoxM1 -deficient pulmonary endothelial cells and identify the FoxM1 transcriptional network of genes essential for endothelial cell proliferation. We will also dissect the mechanisms involved in FoxM1 regulation of p27Kip1. 3. To determine the role of FoxM1 in the mechanism of restoring endothelial integrity. We will address the possibility that FoxM1 plays an important role in re-organizing the endothelial cell-cell junctions following lung vascular injury. We will also examine following LPS-induced vascular injury the ultrastructural defects and the cellular nature of the leaks and repair failure of the pulmonary vasculature in mice with endothelial cell- restricted deficiency of FoxM1.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL085462-04
Application #
7790617
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Moore, Timothy M
Project Start
2007-04-01
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
4
Fiscal Year
2010
Total Cost
$348,750
Indirect Cost
Name
University of Illinois at Chicago
Department
Pharmacology
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Evans, Colin E; Zhao, You-Yang (2017) Molecular Basis of Nitrative Stress in the Pathogenesis of Pulmonary Hypertension. Adv Exp Med Biol 967:33-45
Tran, Khiem A; Zhang, Xianming; Predescu, Dan et al. (2016) Endothelial ?-Catenin Signaling Is Required for Maintaining Adult Blood-Brain Barrier Integrity and Central Nervous System Homeostasis. Circulation 133:177-86
Gu, Xiaowu; Fliesler, Steven J; Zhao, You-Yang et al. (2014) Loss of caveolin-1 causes blood-retinal barrier breakdown, venous enlargement, and mural cell alteration. Am J Pathol 184:541-55
Zhao, Yidan D; Huang, Xiaojia; Yi, Fan et al. (2014) Endothelial FoxM1 mediates bone marrow progenitor cell-induced vascular repair and resolution of inflammation following inflammatory lung injury. Stem Cells 32:1855-64
Huang, Xiaojia; Sun, Kai; Zhao, Yidan D et al. (2014) Human CD34+ progenitor cells freshly isolated from umbilical cord blood attenuate inflammatory lung injury following LPS challenge. PLoS One 9:e88814
Cai, Lei; Yi, Fan; Dai, Zhiyu et al. (2014) Loss of caveolin-1 and adiponectin induces severe inflammatory lung injury following LPS challenge through excessive oxidative/nitrative stress. Am J Physiol Lung Cell Mol Physiol 306:L566-73
Huang, Xiaojia; Zhao, You-Yang (2012) Transgenic expression of FoxM1 promotes endothelial repair following lung injury induced by polymicrobial sepsis in mice. PLoS One 7:e50094
Zhao, Yidan D; Cai, Lei; Mirza, Muhammad K et al. (2012) Protein kinase G-I deficiency induces pulmonary hypertension through Rho A/Rho kinase activation. Am J Pathol 180:2268-75
Mirza, Muhammad K; Sun, Ying; Zhao, Yidan D et al. (2010) FoxM1 regulates re-annealing of endothelial adherens junctions through transcriptional control of beta-catenin expression. J Exp Med 207:1675-85
Zhao, Yidan D; Ohkawara, Hiroshi; Vogel, Stephen M et al. (2010) Bone marrow-derived progenitor cells prevent thrombin-induced increase in lung vascular permeability. Am J Physiol Lung Cell Mol Physiol 298:L36-44

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