Our working concept, over the last several years, has been that the vascular endothelial lining plays an active role in regulating the temporal and spatial patterns of acute inflammatory responses. In particular, previous work in this Project has identified two endothelial- dependent mechanisms especially relevant to neutrophil recruitment -- endothelial-leukocyte adhesion molecule 1 (ELAM-1,-E-SELECTIN) and endothelial-derived interleukin-8 (IL-8). ELAM-1 is an inducible endothelial cell surface glycoprotein that interacts selectively with leukocytes (including neutrophils) that bear a complex carbohydrate ligand (sialyl-Lewis), and supports their adhesion and transmigration in In vitro models. lL-8 is a cytokine, secreted by endothelium and other cells, that functions as a neutrophil activator and chemoattractant, but can also act as an inhibitor of adhesion and transmigration, both in vitro and in vivo. The genes encoding these inflammatory components are normally silent in the uninflamed vascular endothelial cell, but can be strongly induced by certain inflammatory stimuli such as bacterial endotoxin (LPS), interleukin-1 (IL-1) and tumor necrosis factor (TNF), and their products have been detected in inflamed tissues and body fluids in humans and experimental animals. It is our working hypothesis that the regulated expression of these endothelial-dependent mechanisms is important for the orderly development and resolution of acute inflammatory reactions, and that their """"""""dysregulated expression"""""""" may lead to tissue and organ damage. The overall objective of this continuing project, in the next period, will be to develop experimental models (in vitro, in vivo) that make use of molecular biological and genetic approaches to selectively overexpress or underexpress ELAM-1 and IL-8 in vascular endothelial cells, and utilize these models to gain new insights into the role of these endothelial- dependent mechanisms in acute inflammatory disease processes.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL036028-13
Application #
6241892
Study Section
Project Start
1997-07-01
Project End
1998-06-30
Budget Start
1996-10-01
Budget End
1997-09-30
Support Year
13
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02115
Zahr, Alisar; Alcaide, Pilar; Yang, Jinling et al. (2016) Endomucin prevents leukocyte-endothelial cell adhesion and has a critical role under resting and inflammatory conditions. Nat Commun 7:10363
Venkatesh, Deepak; Mruk, Dolores; Herter, Jan M et al. (2016) AKAP9, a Regulator of Microtubule Dynamics, Contributes to Blood-Testis Barrier Function. Am J Pathol 186:270-84
Milstone, David S; Ilyama, Motoi; Chen, Mian et al. (2015) Differential role of an NF-?B transcriptional response element in endothelial versus intimal cell VCAM-1 expression. Circ Res 117:166-77
Cullere, Xavier; Plovie, Eva; Bennett, Paul M et al. (2015) The cerebral cavernous malformation proteins CCM2L and CCM2 prevent the activation of the MAP kinase MEKK3. Proc Natl Acad Sci U S A 112:14284-9
Luscinskas, Francis W; Imhof, Beat A (2014) Introduction for the special issue on new paradigms in leukocyte trafficking, lessons for therapeutics. Semin Immunopathol 36:133-6
Brown, Jonathan D; Lin, Charles Y; Duan, Qiong et al. (2014) NF-?B directs dynamic super enhancer formation in inflammation and atherogenesis. Mol Cell 56:219-231
Mayadas, Tanya N; Cullere, Xavier; Lowell, Clifford A (2014) The multifaceted functions of neutrophils. Annu Rev Pathol 9:181-218
Massaad, Michel J; Oyoshi, Michiko K; Kane, Jennifer et al. (2014) Binding of WIP to actin is essential for T cell actin cytoskeleton integrity and tissue homing. Mol Cell Biol 34:4343-54
Leick, Marion; Azcutia, Veronica; Newton, Gail et al. (2014) Leukocyte recruitment in inflammation: basic concepts and new mechanistic insights based on new models and microscopic imaging technologies. Cell Tissue Res 355:647-56
Azcutia, Veronica; Routledge, Matthew; Williams, Marcie R et al. (2013) CD47 plays a critical role in T-cell recruitment by regulation of LFA-1 and VLA-4 integrin adhesive functions. Mol Biol Cell 24:3358-68

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