The transvascular exchange of fluid and solutes is an essential function of the pulmonary circulation required for the maintenance of lung tissue homeostasis. Increased lung endothelial permeability plays an important role in the pathogenesis of lung inflammatory states such as ARDS. A fundamental, but poorly understood, mechanism of endothelial transport involves the formation of vesicle carriers that transport plasma proteins, such as albumin. The overall objective of Project 1 is to define the nature of the transcellular pathway, its regulation, and its role in the mechanism of increased lung endothelial permeability. The proposed studies have the following specific aims: (i) Specific Aim #1: to determine (i) the segmental differences in the interactions of albumin with pulmonary vascular endothelial cells in vivo via the Albumin Binding Proteins (ABPs) and (ii) transcellular albumin transport in these segments;
Specific Aim #2 : to (i) determine the role of caveolin-1 in regulating pulmonary vascular endothelial barrier function (using CAV 1-/ mice and the siRNA strategy to suppress caveolin-1 expression in lung vascular endothelial cells) and (ii) establish the role of a described population of caveolin-1-independent vesicles in lung vascular endothelial transport;
Specific Aim #3 : to address the role of caveolin-1 in regulating pulmonary microvascular permeability via inter-endothelial junctions;
and Specific Aim #4 : to address the mechanisms of upregulation of caveolin- 1 induced by lipopolysaccharide and its consequences in increasing pulmonary vascular permeability via trannscytosis. Project 1 addresses the mechanisms by which albumin is transported through pulmonary vascular endothelial cells by a transcellular mechanism involving transcytosis under both normal conditions and after sepsis. Thus, Project 1 addresses the mechanisms by which albumin is transported through pulmonary vascular endothelial cells by a transcellular mechanism involving transcytosis under both normal conditions and after sepsis. Since the loss of pulmonary vascular endothelial barrier function is a key factor in the pathogenesis of lung inflammatory disease, such as ARDS, these studies will be important in defining the role of permeability pathways that contribute to protein-rich pulmonary edema. With an advanced understanding of these pathways, it will possible to specifically target these pathways and prevent the endothelial barrier disruption.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL060678-09
Application #
7587434
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2008-03-01
Budget End
2009-02-28
Support Year
9
Fiscal Year
2008
Total Cost
$332,613
Indirect Cost
Name
University of Illinois at Chicago
Department
Type
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Marsboom, Glenn; Rehman, Jalees (2018) Hypoxia Signaling in Vascular Homeostasis. Physiology (Bethesda) 33:328-337
Lv, Yang; Kim, Kyungho; Sheng, Yue et al. (2018) YAP Controls Endothelial Activation and Vascular Inflammation Through TRAF6. Circ Res 123:43-56
Christoforidis, Theodore; Driver, Tom G; Rehman, Jalees et al. (2018) Generation of controllable gaseous H2S concentrations using microfluidics. RSC Adv 8:4078-4083
Di, Anke; Xiong, Shiqin; Ye, Zhiming et al. (2018) The TWIK2 Potassium Efflux Channel in Macrophages Mediates NLRP3 Inflammasome-Induced Inflammation. Immunity 49:56-65.e4
Chen, Zhenlong; D S Oliveira, Suellen; Zimnicka, Adriana M et al. (2018) Reciprocal regulation of eNOS and caveolin-1 functions in endothelial cells. Mol Biol Cell 29:1190-1202
Le Master, Elizabeth; Huang, Ru-Ting; Zhang, Chongxu et al. (2018) Proatherogenic Flow Increases Endothelial Stiffness via Enhanced CD36-Mediated Uptake of Oxidized Low-Density Lipoproteins. Arterioscler Thromb Vasc Biol 38:64-75
Marsboom, Glenn; Chen, Zhenlong; Yuan, Yang et al. (2017) Aberrant Caveolin-1-Mediated Smad Signaling and Proliferation Identified by Analysis of Adenine 474 Deletion Mutation (c.474delA) in Patient Fibroblasts: A New Perspective in the Mechanism of Pulmonary Hypertension. Mol Biol Cell :
Yazbeck, Pascal; Tauseef, Mohammad; Kruse, Kevin et al. (2017) STIM1 Phosphorylation at Y361 Recruits Orai1 to STIM1 Puncta and Induces Ca2+ Entry. Sci Rep 7:42758
Gong, Haixia; Liu, Menglin; Klomp, Jeff et al. (2017) Method for Dual Viral Vector Mediated CRISPR-Cas9 Gene Disruption in Primary Human Endothelial Cells. Sci Rep 7:42127
Komarova, Yulia A; Kruse, Kevin; Mehta, Dolly et al. (2017) Protein Interactions at Endothelial Junctions and Signaling Mechanisms Regulating Endothelial Permeability. Circ Res 120:179-206

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