This program proposes an interdisciplinary effort to broaden our understanding of the roles of mediators such as eicosanoids and nitric oxide in the pathogenesis of cerebrovascular thrombosis and brain injury and to enhance our knowledge on the regulation on the regulation and augmentation of their synthesis. Our major goal is to elucidate the fundamental mechanisms by which important endothelial and neuronal genes are regulated and to bring these basic investigations in clinical applications in improved care of patients with cerebrovascular thrombosis and brain injury. Substantial progresses have been made during the previous and present funding periods. These progresses contribute significantly to the rapid advance in this area of research. In this renewal application, we will pursue ongoing project ongoing projects and add new areas of research. Four projects and two core units are proposed. . Project 1, Regulation of Eicosanoid Biosynthesis, is a continuing project aimed at characterization of the transcriptional regulation of endothelial COX-1 and PGI synthase genes. Project 2, Induction of NOS-3 and COX-2 by Vasoprotective agents, is an extension of project 1.
It aims at elucidating the mechanism by which lysophosphatidylcholine and estrogen induces housekeeping NOS-3 and inducible COX-2 genes. Project 3, Role of Cox-2 in Brain Trauma Pathophysiology, proposes to test the hypothesis that COX-2 induction contributes to traumatic brain injury pathophysiology, and anti- inflammatory agents, methylprednisone and IL-10 attenuates COX-2 expression. Project 4, Structure-Function Relationships of TXA2 and PGI2 Receptors, is an extension of project 2 of the current program. It proposes to use a combination of biochemical, biophysical and molecular genetic techniques to map the ligand binding sites of these two receptors. Core A provides administrative coordination and Core B laboratory support for all projects. Thus, the scope of this program ranges from structural biology, cellular and molecular biology to in vivo animal models and there exists an exciting potential for a rapid application of basic information to clinical management of stroke and brain injury and vice versa. The program involves professional personnel who have a long standing interest in thrombosis and stroke research with diverse but complementary expertises in vascular biology, hematology, neurology, neurobiology, biochemistry, cell-molecular biology, structural biology, enzymology and pharmacology. There is an active interaction among investigators. This program has a tract record for cultivating trainees and young investigators. It is intended that this program will enable several laboratories to work individually and together to achieve the highest degree of innovating and productivity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Specialized Center (P50)
Project #
5P50NS023327-16
Application #
6351798
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Jacobs, Tom P
Project Start
1985-08-01
Project End
2004-01-31
Budget Start
2001-02-01
Budget End
2002-01-31
Support Year
16
Fiscal Year
2001
Total Cost
$1,042,922
Indirect Cost
Name
University of Texas Health Science Center Houston
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Houston
State
TX
Country
United States
Zip Code
77225
Chen, Pei-Feng; Wu, Kenneth K (2009) Two synthetic peptides corresponding to the proximal heme-binding domain and CD1 domain of human endothelial nitric-oxide synthase inhibit the oxygenase activity by interacting with CaM. Arch Biochem Biophys 486:132-40
Wu, Jui-Sheng; Cheung, Wai-Mui; Tsai, Yau-Sheng et al. (2009) Ligand-activated peroxisome proliferator-activated receptor-gamma protects against ischemic cerebral infarction and neuronal apoptosis by 14-3-3 epsilon upregulation. Circulation 119:1124-34
Liou, Jun-Yang; Ellent, David P; Lee, Sang et al. (2007) Cyclooxygenase-2-derived prostaglandin e2 protects mouse embryonic stem cells from apoptosis. Stem Cells 25:1096-103
Wu, Kenneth K (2006) Transcription-based COX-2 inhibition: a therapeutic strategy. Thromb Haemost 96:417-22
Liou, Jun-Yang; Lee, Sang; Ghelani, Dipak et al. (2006) Protection of endothelial survival by peroxisome proliferator-activated receptor-delta mediated 14-3-3 upregulation. Arterioscler Thromb Vasc Biol 26:1481-7
Cieslik, Katarzyna A; Deng, Wu-Guo; Wu, Kenneth K (2006) Essential role of C-Rel in nitric-oxide synthase-2 transcriptional activation: time-dependent control by salicylate. Mol Pharmacol 70:2004-14
Deng, Wu-Guo; Tang, Shao-Tzu; Tseng, Hui-Ping et al. (2006) Melatonin suppresses macrophage cyclooxygenase-2 and inducible nitric oxide synthase expression by inhibiting p52 acetylation and binding. Blood 108:518-24
Wu, Kenneth K (2006) Analysis of protein-DNA binding by streptavidin-agarose pulldown. Methods Mol Biol 338:281-90
Lin, Teng-Nan; Cheung, Wai-Mui; Wu, Jui-Sheng et al. (2006) 15d-prostaglandin J2 protects brain from ischemia-reperfusion injury. Arterioscler Thromb Vasc Biol 26:481-7
Liou, Jun-Yang; Aleksic, Nena; Chen, Shu-Fen et al. (2005) Mitochondrial localization of cyclooxygenase-2 and calcium-independent phospholipase A2 in human cancer cells: implication in apoptosis resistance. Exp Cell Res 306:75-84

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