Latanoprost, a chemical analogue of PGF2alpha, is currently the number one drug for the treatment of primary open angle glaucoma, yet relatively little is known about its basic mechanisms of action. The goal of this project is to define the molecular mechanisms of action that underlie the pharmacological effects of PGF2alpha latanoprost, and other PGF2alpha analogues on the eye. The overall hypothesis is that the pharmacological effects of these agents on the eye are mediated by interactions with one or more of the FP prostanoid receptor alternative mRNA splice variants or isoforms. To this end we have proposed four major specific aims.
The first aim i s to define the second messenger pathways and regulation of the FP prostanoid receptor isoforms. In this regard, we have recently discovered that one of the isoforms, the FPbeta, activates Tcf/ beta-catenin mediated transcriptional activation. This is very significant because it is the first documented link between G-protein coupled receptor activation and the Tcf/beta-catenin signaling pathway, which is known to be involved with development and transformation.
Our second aim will be to identify novel proteins that interact directly or are regulated by FP receptor activation. The identification of downstream targets, particularly those which may be regulated by transcriptional activation, could provide important clues for understanding the cellular physiology of FP receptor activation.
Our third aim i s to clone the human and mouse orthologs of the FPbeta isoform. We have recently identified one human FP receptor alternative splice variant and clearly the cloning of a human FPbeta isoform is important for understanding the potential significance of this isoform in humans. As a final aim we propose to examine the localization of FP receptors in ocular tissues and to integrate our findings from our first three aims with understanding FP receptor signaling in the eye. As detailed in this application we have well documented evidence of the feasibility of this work. We further believe that it will contribute to an improved understanding of the molecular pharmacology of the FP prostanoid receptors and the physiological/pharmacological role of these receptors in the eye.
|Ji, R; Sanchez, C M; Chou, C L et al. (2012) Prostanoid EP? receptors mediate up-regulation of the orphan nuclear receptor Nurr1 by cAMP-independent activation of protein kinase A, CREB and NF-?B. Br J Pharmacol 166:1033-46|
|Ji, Ruyue; Chou, Chih-Ling; Xu, Wei et al. (2010) EP1 prostanoid receptor coupling to G i/o up-regulates the expression of hypoxia-inducible factor-1 alpha through activation of a phosphoinositide-3 kinase signaling pathway. Mol Pharmacol 77:1025-36|
|Hutchinson, Anthony J; Coons, Serena C; Chou, Chih-Ling et al. (2010) Induction of angiogenic immediate early genes by activation of FP prostanoid receptors in cultured human ciliary smooth muscle cells. Curr Eye Res 35:408-18|
|Xu, Wei; Chou, Chih-Ling; Israel, Davelene D et al. (2009) PGF(2alpha) stimulates FP prostanoid receptor mediated crosstalk between Ras/Raf signaling and Tcf transcriptional activation. Biochem Biophys Res Commun 381:625-9|
|Hutchinson, Anthony J; Chou, Chih-Ling; Israel, Davelene D et al. (2009) Activation of EP2 prostanoid receptors in human glial cell lines stimulates the secretion of BDNF. Neurochem Int 54:439-46|
|Israel, Davelene D; Regan, John W (2009) EP(3) prostanoid receptor isoforms utilize distinct mechanisms to regulate ERK 1/2 activation. Biochim Biophys Acta 1791:238-45|
|Taniguchi, Tomoko; Fujino, Hiromichi; Israel, Davelene D et al. (2008) Human EP3(I) prostanoid receptor induces VEGF and VEGF receptor-1 mRNA expression. Biochem Biophys Res Commun 377:1173-8|
|Xu, Wei; Chou, Chih-Ling; Sun, Haipeng et al. (2008) FP prostanoid receptor-mediated induction of the expression of early growth response factor-1 by activation of a Ras/Raf/mitogen-activated protein kinase signaling cascade. Mol Pharmacol 73:111-8|
|Fujino, Hiromichi; Chen, Xiao-bo; Regan, John W et al. (2007) Indomethacin decreases EP2 prostanoid receptor expression in colon cancer cells. Biochem Biophys Res Commun 359:568-73|
|Chen, X-B; Regan, J W (2006) Activation of the human FP prostanoid receptor disrupts mitosis progression and generates aneuploidy and polyploidy. Cell Mol Life Sci 63:112-21|
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