The cyclooxygenase (COX) enzymes are differentially regulated and expressed in various developmental and pathological situations. The applicant's laboratory has had a long standing interest in the biology of these isoenzymes and the principal investigator is one of the first to clone the cDNA for cyclooxygenase. This competitive renewal attempts to critically examine the hypothesis that post-transcriptional mechanisms contribute to the dysregulated expression of cyclooxygenase gene and that the activation of the cyclooxygenase pathway regulates distinct signaling pathways, viz., the well characterized extracellular prostanoid dependent and the novel, intracellular, non-prostanoid dependent pathways.
Two specific aims are delineated. The applicant wishes to further examine at the molecular level the regulation of COX-2 expression at the post transcriptional level. Mechanisms that involve the basal and induced COX-2 messenger RNA stabilization/ destabilization will be defined at the level of messenger RNA structure and the associate polypeptide complexes. Furthermore, the ability of signaling pathways to influence COX-2 mRNA metabolism will be characterized. In addition, unique post-transcriptional regulatory mechanisms of COX-2 regulation in mammary carcinoma cells will be defined. The second specific aim is set out to define the molecular basis of COX isoenzyme signaling via the prostanoid independent pathway. The ability of COX 1 and 2 isoenzyme and the active site mutants which are deficient in prostanoid synthesis will be assessed that are involved with the regulation of endothelial cell growth apoptosis and tumorigenic transformation. Constitutively expressed COX-1 and inducibly expressed COX-2 in the endothelial cell system will be used to isolate specific COX induced genes, thus, molecularly defining the down stream targets of specific COX signaling pathways.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL049094-08
Application #
6125918
Study Section
Pathology A Study Section (PTHA)
Program Officer
Laughlin, Maren R
Project Start
1993-09-01
Project End
2002-11-30
Budget Start
1999-12-01
Budget End
2000-11-30
Support Year
8
Fiscal Year
2000
Total Cost
$264,157
Indirect Cost
Name
University of Connecticut
Department
Physiology
Type
Schools of Dentistry
DUNS #
City
Farmington
State
CT
Country
United States
Zip Code
06030
Wagschal, Alexandre; Najafi-Shoushtari, S Hani; Wang, Lifeng et al. (2015) Genome-wide identification of microRNAs regulating cholesterol and triglyceride homeostasis. Nat Med 21:1290-7
Chang, Sung-Hee; Elemento, Olivier; Zhang, Jiasheng et al. (2014) ELAVL1 regulates alternative splicing of eIF4E transporter to promote postnatal angiogenesis. Proc Natl Acad Sci U S A 111:18309-14
Li, Xi; Lu, Yi-Chien; Dai, Kezhi et al. (2014) Elavl1a regulates zebrafish erythropoiesis via posttranscriptional control of gata1. Blood 123:1384-92
Lu, Yi-Chien; Chang, Sung-Hee; Hafner, Markus et al. (2014) ELAVL1 modulates transcriptome-wide miRNA binding in murine macrophages. Cell Rep 9:2330-43
Giammanco, Antonina; Blanc, Valerie; Montenegro, Grace et al. (2014) Intestinal epithelial HuR modulates distinct pathways of proliferation and apoptosis and attenuates small intestinal and colonic tumor development. Cancer Res 74:5322-35
Chang, Sung-Hee; Lu, Yi-Chien; Li, Xi et al. (2013) Antagonistic function of the RNA-binding protein HuR and miR-200b in post-transcriptional regulation of vascular endothelial growth factor-A expression and angiogenesis. J Biol Chem 288:4908-21
Hla, Timothy; Dannenberg, Andrew J (2012) Sphingolipid signaling in metabolic disorders. Cell Metab 16:420-34
Chang, Sung-Hee; Hla, Timothy (2011) Gene regulation by RNA binding proteins and microRNAs in angiogenesis. Trends Mol Med 17:650-8
Skoura, Athanasia; Hla, Timothy (2009) Regulation of vascular physiology and pathology by the S1P2 receptor subtype. Cardiovasc Res 82:221-8
Ghosh, Mallika; Aguila, Hector Leonardo; Michaud, Jason et al. (2009) Essential role of the RNA-binding protein HuR in progenitor cell survival in mice. J Clin Invest 119:3530-43

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