The Expression and Function of Native EP and FP Prostanoid Receptors in Cultured Cells Derived from the Human Brain and Eye

Persistent Link:
http://hdl.handle.net/10150/196126
Title:
The Expression and Function of Native EP and FP Prostanoid Receptors in Cultured Cells Derived from the Human Brain and Eye
Author:
Hutchinson, Anthony Jason
Issue Date:
2009
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
The prostaglandins comprise a group of bioactive lipids generated from arachidonic acid by cyclooxygenases and cell type-specific prostaglandin and thromboxane synthases. Prostaglandins mediate local cell signaling interactions by activation of G-protein coupled prostanoid receptors. Because the prostaglandins and their receptors are active in all tissues, they have an extraordinarily broad spectrum of physiological and pathophysiological functions that have hampered the development of safe prostanoid-based medications. This situation has emphasized the importance of understanding the functional properties of the prostanoid receptors and developing selective ligands capable of being used in patient care.The aims of this project were to identify novel regulatory functions of endogenous EP and FP prostanoid receptors in cultured human cells. Our results show that activation of EP<sub>2</sub> receptors in human microglia and astrocytes led to increased secretion of BDNF, a growth factor that regulates the survival of neurons. In the same cell lines, FP receptors regulate the induction of TNF-&alpha; gene expression through a classic G<sub>q</sub>-PKC pathway. In microglia these FP receptors also stimulate a novel signaling crosstalk mechanism involving the up-regulation of TCF transcriptional function by Raf kinases, which culminates in the expression of the angiogenic inducer Cyr61. FP receptors also regulate the induction of angiogenic immediate early genes in cultured ciliary muscle cells, which may constitute the early steps in a mechanism by which commercial FP agonists reduce intraocular pressure in glaucoma therapy.The up-regulation of BDNF through glial EP<sub>2</sub> receptors constitutes a mechanism by which elevated PGE<sub>2</sub> in the inflamed brain might elicit either healing processes in the brain or neuronal apoptosis. On the other hand, induction of TNF-&alpha; and Cyr61 by glial FP receptors may mediate neuroinflammation and may also contribute to glioma tumor growth. Stimulation of FP receptors in the ciliary muscle leads to the induction of immediate early genes capable of coordinating tissue remodeling processes that have been previously documented. The results of these studies suggest novel regulatory functions of the prostanoid receptors in the brain and eye. Furthermore, these findings provide insight on how the selective modulation of the EP<sub>2</sub> and FP receptors might be therapeutically advantageous.
Type:
text; Electronic Dissertation
Keywords:
Astrocyte; Ciliary muscle; G-protein coupled receptor; Microglia; Prostanoid
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Neuroscience; Graduate College
Degree Grantor:
University of Arizona
Advisor:
Regan, John W.
Committee Chair:
Regan, John W.

Full metadata record

DC FieldValue Language
dc.language.isoENen_US
dc.titleThe Expression and Function of Native EP and FP Prostanoid Receptors in Cultured Cells Derived from the Human Brain and Eyeen_US
dc.creatorHutchinson, Anthony Jasonen_US
dc.contributor.authorHutchinson, Anthony Jasonen_US
dc.date.issued2009en_US
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.abstractThe prostaglandins comprise a group of bioactive lipids generated from arachidonic acid by cyclooxygenases and cell type-specific prostaglandin and thromboxane synthases. Prostaglandins mediate local cell signaling interactions by activation of G-protein coupled prostanoid receptors. Because the prostaglandins and their receptors are active in all tissues, they have an extraordinarily broad spectrum of physiological and pathophysiological functions that have hampered the development of safe prostanoid-based medications. This situation has emphasized the importance of understanding the functional properties of the prostanoid receptors and developing selective ligands capable of being used in patient care.The aims of this project were to identify novel regulatory functions of endogenous EP and FP prostanoid receptors in cultured human cells. Our results show that activation of EP<sub>2</sub> receptors in human microglia and astrocytes led to increased secretion of BDNF, a growth factor that regulates the survival of neurons. In the same cell lines, FP receptors regulate the induction of TNF-&alpha; gene expression through a classic G<sub>q</sub>-PKC pathway. In microglia these FP receptors also stimulate a novel signaling crosstalk mechanism involving the up-regulation of TCF transcriptional function by Raf kinases, which culminates in the expression of the angiogenic inducer Cyr61. FP receptors also regulate the induction of angiogenic immediate early genes in cultured ciliary muscle cells, which may constitute the early steps in a mechanism by which commercial FP agonists reduce intraocular pressure in glaucoma therapy.The up-regulation of BDNF through glial EP<sub>2</sub> receptors constitutes a mechanism by which elevated PGE<sub>2</sub> in the inflamed brain might elicit either healing processes in the brain or neuronal apoptosis. On the other hand, induction of TNF-&alpha; and Cyr61 by glial FP receptors may mediate neuroinflammation and may also contribute to glioma tumor growth. Stimulation of FP receptors in the ciliary muscle leads to the induction of immediate early genes capable of coordinating tissue remodeling processes that have been previously documented. The results of these studies suggest novel regulatory functions of the prostanoid receptors in the brain and eye. Furthermore, these findings provide insight on how the selective modulation of the EP<sub>2</sub> and FP receptors might be therapeutically advantageous.en_US
dc.typetexten_US
dc.typeElectronic Dissertationen_US
dc.subjectAstrocyteen_US
dc.subjectCiliary muscleen_US
dc.subjectG-protein coupled receptoren_US
dc.subjectMicrogliaen_US
dc.subjectProstanoiden_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineNeuroscienceen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorRegan, John W.en_US
dc.contributor.chairRegan, John W.en_US
dc.contributor.committeememberGordon, Hermanen_US
dc.contributor.committeememberNighorn, Alanen_US
dc.contributor.committeememberVanderah, Todd W.en_US
dc.contributor.committeememberWilson, Jean M.en_US
dc.identifier.proquest10278en_US
dc.identifier.oclc659750892en_US
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