This Program Project entitled """"""""Signaling of Endothelial Permeability and Lung Vascular Injury"""""""" addresses signaling pathways mediating increased endothelial permeability and microvascular injury. The overall objective of the Program Project is to define the regulatory signaling pathways using multi-disciplinary strategies involving investigators from Departments of Pharmacology, Biological Chemistry, Anesthesiology, and Medicine. In Project 1, we will address signaling mechanisms of increased endothelial permeability involving transcytosis in endothelial cells. These studies will define regulation of this pathway and its functional significance in the pathophysiology of increased lung microvascular permeability. In Project 2, we will study regulation of nitric oxide (NO) oxide (NO) production by the recently cloned carboxypeptidases D and M localized in plasma membranes of monocyte/macrophage and endothelial cells. We will study the function of these regulatory enzymes in providing the arginine substrate for NO production and the autocrine and paracrine role of No in signaling the increase in endothelial permeability. In Project 3, we will study the interactions between the thrombin receptor (PAR-1) and other PARs and specific G-proteins to which they are coupled in endothelial cells. We will determine whether expression of sequence-specific peptides interfering with PAR-1-G protein signaling can prevent thrombin-activated increase in endothelial permeability and expression of endothelial adhesivity (via P-selectin and ICAM-1 expression). The three projects will be supported by three cores: Administrative, Cell Culture and Hybridoma and Biochemistry/Molecular Resources which will integrate the objectives of each project to the program's overall objective. The goal of addressing the signaling mechanisms regulatory pulmonary vascular endothelial permeability will assist in the development of novel strategies aimed at preventing microvessel injury in lungs.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL060678-05
Application #
6726827
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Denholm, Elizabeth M
Project Start
2000-03-08
Project End
2005-02-28
Budget Start
2004-03-01
Budget End
2005-02-28
Support Year
5
Fiscal Year
2004
Total Cost
$1,339,914
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
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