EICOSANOIDS AND NO IN CEREBROVASCULAR THROMBOSIS

Summary

Principal Investigator: Kenneth Wu
Abstract: 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.
Funding Period: 1985-08-01 - 2005-01-31
more information: NIH RePORT

Top Publications

  1. pmc Ligand-activated peroxisome proliferator-activated receptor-gamma protects against ischemic cerebral infarction and neuronal apoptosis by 14-3-3 epsilon upregulation
    Jui Sheng Wu
    Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
    Circulation 119:1124-34. 2009
  2. ncbi Differential cyclooxygenase-2 transcriptional control in proliferating versus quiescent fibroblasts
    Kenneth K Wu
    Vascular Biology Research Center at Institute of Molecular Medicine, University of Texas Health Science Center at Houston, TX, USA
    Prostaglandins Other Lipid Mediat 83:175-81. 2007
  3. pmc 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
    Pei Feng Chen
    Vascular Biology Research Center, Department of Internal Medicine, The University of Texas Health Science Center at Houston, TX, USA
    Arch Biochem Biophys 486:132-40. 2009
  4. ncbi Cyclooxygenase-2-derived prostaglandin e2 protects mouse embryonic stem cells from apoptosis
    Jun Yang Liou
    Division of Hematology and Vascular Biology Research Center, The University of Texas Health Science Center at Houston, 6431 Fannin, MSB 5 016, Houston, Texas 77030, USA
    Stem Cells 25:1096-103. 2007
  5. ncbi Transcription-based COX-2 inhibition: a therapeutic strategy
    Kenneth K Wu
    Vascular Biology Research Center and Division of Hematology, Department of Medicine, The University of Texas Health Science Center at Houston, Texas 77030, USA
    Thromb Haemost 96:417-22. 2006
  6. ncbi Essential role of C-Rel in nitric-oxide synthase-2 transcriptional activation: time-dependent control by salicylate
    Katarzyna A Cieslik
    Vascular Biology Research Center at the Brown Foundation Institute of Molecular Medicine and Division of Hematology, University of Texas Health Science Center at Houston, Houston, Texas 77030, USA
    Mol Pharmacol 70:2004-14. 2006
  7. ncbi Analysis of protein-DNA binding by streptavidin-agarose pulldown
    Kenneth K Wu
    Division of Hematology, Institute of Molecular Medicine, University of Texas Health Science Center, Houston, TX, USA
    Methods Mol Biol 338:281-90. 2006
  8. ncbi Protection of endothelial survival by peroxisome proliferator-activated receptor-delta mediated 14-3-3 upregulation
    Jun Yang Liou
    Vascular Biology Research Center, Brown Foundation Institute of Molecular Medicine, Houston, TX 77030 1503, USA
    Arterioscler Thromb Vasc Biol 26:1481-7. 2006
  9. pmc Melatonin suppresses macrophage cyclooxygenase-2 and inducible nitric oxide synthase expression by inhibiting p52 acetylation and binding
    Wu Guo Deng
    Vascular Biology Research Center, Institute of Molecular Medicine and Division of Hematology, Department of Internal Medicine, The University of Texas Health Science Center at Houston, 77030, USA
    Blood 108:518-24. 2006
  10. ncbi 15d-prostaglandin J2 protects brain from ischemia-reperfusion injury
    Teng Nan Lin
    Neuroscience Division, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
    Arterioscler Thromb Vasc Biol 26:481-7. 2006

Scientific Experts

  • Pei Feng Chen
  • Kenneth Wu
  • Jun Yang Liou
  • Katarzyna A Cieslik
  • Jui Sheng Wu
  • Teng Nan Lin
  • Song Kun Shyue
  • Wu Guo Deng
  • Wai Mui Cheung
  • Jin Jer Chen
  • Sang Lee
  • Y Eugene Chen
  • Nobuyo Maeda
  • Wen Hsuan Fong
  • Hsin Da Tsai
  • Yu Chang Chen
  • Yi Tong Chen
  • Yau Sheng Tsai
  • Nena Matijevic
  • David P Ellent
  • Jennifer Goldsby
  • Bor Sheng Ko
  • Jaou Chen Huang
  • Nevenka Matijevic-Aleksic
  • Dipak Ghelani
  • Hui Ping Tseng
  • Jean Ju Chen
  • Shao Tzu Tang
  • Heng Lin
  • Shu Fen Chen
  • Ying Zhu
  • Tsai Jung Han
  • Mikhail Shtivelband
  • Nena Aleksic

Detail Information

Publications15

  1. pmc Ligand-activated peroxisome proliferator-activated receptor-gamma protects against ischemic cerebral infarction and neuronal apoptosis by 14-3-3 epsilon upregulation
    Jui Sheng Wu
    Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
    Circulation 119:1124-34. 2009
    ..Their protective actions are considered to be peroxisome proliferator-activated receptor-gamma (PPAR-gamma)-dependent; however, it is unclear how PPAR-gamma activation confers resistance to ischemia-reperfusion injury...
  2. ncbi Differential cyclooxygenase-2 transcriptional control in proliferating versus quiescent fibroblasts
    Kenneth K Wu
    Vascular Biology Research Center at Institute of Molecular Medicine, University of Texas Health Science Center at Houston, TX, USA
    Prostaglandins Other Lipid Mediat 83:175-81. 2007
    ....
  3. pmc 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
    Pei Feng Chen
    Vascular Biology Research Center, Department of Internal Medicine, The University of Texas Health Science Center at Houston, TX, USA
    Arch Biochem Biophys 486:132-40. 2009
    ..The results suggest that multiple regions of eNOS might interact with CaM with differential Ca(2+) sensitivity in vivo. A possible mechanism in regulating eNOS activation and deactivation is proposed...
  4. ncbi Cyclooxygenase-2-derived prostaglandin e2 protects mouse embryonic stem cells from apoptosis
    Jun Yang Liou
    Division of Hematology and Vascular Biology Research Center, The University of Texas Health Science Center at Houston, 6431 Fannin, MSB 5 016, Houston, Texas 77030, USA
    Stem Cells 25:1096-103. 2007
    ..Disclosure of potential conflicts of interest is found at the end of this article...
  5. ncbi Transcription-based COX-2 inhibition: a therapeutic strategy
    Kenneth K Wu
    Vascular Biology Research Center and Division of Hematology, Department of Medicine, The University of Texas Health Science Center at Houston, Texas 77030, USA
    Thromb Haemost 96:417-22. 2006
    ..RSK phosphorylates C/EBPbeta and stimulates its binding to enhancer elements. We propose that RSK1/2 is a potential target for screening drugs with novel anti-inflammatory and anti-neoplastic therapeutic potentials...
  6. ncbi Essential role of C-Rel in nitric-oxide synthase-2 transcriptional activation: time-dependent control by salicylate
    Katarzyna A Cieslik
    Vascular Biology Research Center at the Brown Foundation Institute of Molecular Medicine and Division of Hematology, University of Texas Health Science Center at Houston, Houston, Texas 77030, USA
    Mol Pharmacol 70:2004-14. 2006
    ..We propose that salicylate inhibits C/EBPbeta binding at 4 h and C-Rel binding at 8 and 24 h by targeting related kinases...
  7. ncbi Analysis of protein-DNA binding by streptavidin-agarose pulldown
    Kenneth K Wu
    Division of Hematology, Institute of Molecular Medicine, University of Texas Health Science Center, Houston, TX, USA
    Methods Mol Biol 338:281-90. 2006
    ..This method has been shown to be useful in determining the regulation of binding of transactivators, p300/CBP, and associated proteins to the cyclooxygenase-2 (COX-2) promoter...
  8. ncbi Protection of endothelial survival by peroxisome proliferator-activated receptor-delta mediated 14-3-3 upregulation
    Jun Yang Liou
    Vascular Biology Research Center, Brown Foundation Institute of Molecular Medicine, Houston, TX 77030 1503, USA
    Arterioscler Thromb Vasc Biol 26:1481-7. 2006
    ..To determine the role of prostacyclin (PGI2) in protecting endothelial cells (ECs) from apoptosis and elucidate the protective mechanism...
  9. pmc Melatonin suppresses macrophage cyclooxygenase-2 and inducible nitric oxide synthase expression by inhibiting p52 acetylation and binding
    Wu Guo Deng
    Vascular Biology Research Center, Institute of Molecular Medicine and Division of Hematology, Department of Internal Medicine, The University of Texas Health Science Center at Houston, 77030, USA
    Blood 108:518-24. 2006
    ..These results suggest that melatonin inhibits COX-2 and iNOS transcriptional activation by inhibiting p300 HAT activity, thereby suppressing p52 acetylation, binding, and transactivation...
  10. ncbi 15d-prostaglandin J2 protects brain from ischemia-reperfusion injury
    Teng Nan Lin
    Neuroscience Division, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
    Arterioscler Thromb Vasc Biol 26:481-7. 2006
    ..The aim of this study is to assess the effect of 15d-PGJ2 on neuroprotection...
  11. ncbi Cellular and molecular biology of prostacyclin synthase
    Kenneth K Wu
    Vascular Biology Research Center, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
    Biochem Biophys Res Commun 338:45-52. 2005
    ..PGIS coupling with COX-2 has been shown to play an important role in vascular protection, embryo development and implantation, and cancer growth...
  12. ncbi Mitochondrial localization of cyclooxygenase-2 and calcium-independent phospholipase A2 in human cancer cells: implication in apoptosis resistance
    Jun Yang Liou
    Vascular Biology Research Center and Division of Hematology, Institute of, Molecular Medicine and Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030 1503, USA
    Exp Cell Res 306:75-84. 2005
    ..These results suggest that mitochondrial COX-2 in cancer cells confer resistance to apoptosis by reducing the proapoptotic arachidonic acid...
  13. ncbi Inhibition of p90 ribosomal S6 kinase-mediated CCAAT/enhancer-binding protein beta activation and cyclooxygenase-2 expression by salicylate
    Katarzyna A Cieslik
    Vascular Biology Research Center and Division of Hematology, Brown Foundation Institute of Molecular Medicine and Medical School, The University of Texas Health Science Center and Texas Heart Institute, Houston, Texas 77030 1503, USA
    J Biol Chem 280:18411-7. 2005
    ..We conclude that salicylate inhibits C/EBPbeta-mediated COX-2 transcriptional activation by blocking RSK activity and Ras signaling pathway...
  14. ncbi Transcriptional Control of COX-2 via C/EBPbeta
    Kenneth K Wu
    Vascular Biology Research Center, Institute of Molecular Medicine and Division of Hematology, University of Texas Health Science Center at Houston, 6431 Fannin, MSB 5 016, Houston, TX 77030, USA
    Arterioscler Thromb Vasc Biol 25:679-85. 2005
    ..The recent progress sheds light on the pathophysiological mechanisms of COX-2 and new transcription-based strategy for controlling COX-2 overexpression and COX-2-mediated cardiovascular diseases...
  15. ncbi Control of cyclooxygenase-2 transcriptional activation by pro-inflammatory mediators
    K K Wu
    Vascular Biology Research Center and Division of Hematology, Department of Internal Medicine, Institute of Molecular Medicine and Medical School, University of Texas Health Science Center at Houston, TX 77030, USA
    Prostaglandins Leukot Essent Fatty Acids 72:89-93. 2005
    ....