Persistent Link:
http://hdl.handle.net/10150/195533
Title:
Selenium Effects on the Trabecular Meshwork
Author:
Conley, Shannon Martha
Issue Date:
2005
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:
Epidemiological evidence indicates that selenium supplementation may increase risk for ocular hypertension and glaucoma. The purpose of this project was to determine the effects of selenium on the conventional "trabecular" aqueous outflow pathway, a likely site of pathology for glaucoma. Human trabecular meshwork (HTM) cells and human umbilical vein endothelial cells (HUVECs) were treated with selenium (MSeA) at or near physiologically relevant concentrations. Selenium uptake by cells was monitored using mass spectrometry. While detectible changes in intracellular selenium were observed after exposure to 1-10 uM MSeA for 24 hours, the majority remained in the conditioned medium. The high concentrations of extracellular selenium we observed raised the possibility that selenium has an extracellular target.To investigate the role of selenium in extracellular matrix turnover, I examined alterations in protein secretion and intracellular signaling. MSeA treatment (5-10 uM) led to a significant decrease in the secretion of matrix metalloproteinase -2 and its inhibitor after 6-24 hours and to a dose-dependent decrease in kinase signaling. Later, I investigated the possibility that integrins are an extracellular target of selenium by monitoring morphological changes in HTM cells and by treating them with divalent cations. MSeA stimulated morphological changes consistent with a decrease in integrin function. These occurred before (less than 3 hours) alterations in protein secretion and intracellular signaling (3-6 hours). Zinc treatment prevented MSeA-mediated alterations in protein secretion and changes in cell-matrix adhesion.Finally markers of HTM cell homeostasis were examined. MSeA treatment (5 uM) led to a 60% decrease in protein synthesis after 3 hours and a 60% reduction in protein secretion, without causing significant alterations in cell viability and total ATP. To assess the physiological relevance of my results, anterior segments were perfused with MSeA to determine its effects on aqueous outflow facility. Preliminary results suggest that MSeA leads to a decrease in outflow facility.The combination of MSeA-induced decreases in several indicators of HTM cell homeostasis (without adversely effects on cell viability at physiologically relevant doses) and decreases in outflow facility provide a possible mechanism for selenium-associated ocular hypertension.
Type:
text; Electronic Dissertation
Keywords:
Selenium; Trabecular Meshwork; Glaucoma; Angiogenesis; Extracellular Matrix
Degree Name:
PhD
Degree Level:
doctoral
Degree Program:
Pharmacology & Toxicology; Graduate College
Degree Grantor:
University of Arizona
Advisor:
Stamer, W. Daniel; Yool, Andrea J.
Committee Chair:
Stamer, W. Daniel; Yool, Andrea J.

Full metadata record

DC FieldValue Language
dc.language.isoENen_US
dc.titleSelenium Effects on the Trabecular Meshworken_US
dc.creatorConley, Shannon Marthaen_US
dc.contributor.authorConley, Shannon Marthaen_US
dc.date.issued2005en_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.abstractEpidemiological evidence indicates that selenium supplementation may increase risk for ocular hypertension and glaucoma. The purpose of this project was to determine the effects of selenium on the conventional "trabecular" aqueous outflow pathway, a likely site of pathology for glaucoma. Human trabecular meshwork (HTM) cells and human umbilical vein endothelial cells (HUVECs) were treated with selenium (MSeA) at or near physiologically relevant concentrations. Selenium uptake by cells was monitored using mass spectrometry. While detectible changes in intracellular selenium were observed after exposure to 1-10 uM MSeA for 24 hours, the majority remained in the conditioned medium. The high concentrations of extracellular selenium we observed raised the possibility that selenium has an extracellular target.To investigate the role of selenium in extracellular matrix turnover, I examined alterations in protein secretion and intracellular signaling. MSeA treatment (5-10 uM) led to a significant decrease in the secretion of matrix metalloproteinase -2 and its inhibitor after 6-24 hours and to a dose-dependent decrease in kinase signaling. Later, I investigated the possibility that integrins are an extracellular target of selenium by monitoring morphological changes in HTM cells and by treating them with divalent cations. MSeA stimulated morphological changes consistent with a decrease in integrin function. These occurred before (less than 3 hours) alterations in protein secretion and intracellular signaling (3-6 hours). Zinc treatment prevented MSeA-mediated alterations in protein secretion and changes in cell-matrix adhesion.Finally markers of HTM cell homeostasis were examined. MSeA treatment (5 uM) led to a 60% decrease in protein synthesis after 3 hours and a 60% reduction in protein secretion, without causing significant alterations in cell viability and total ATP. To assess the physiological relevance of my results, anterior segments were perfused with MSeA to determine its effects on aqueous outflow facility. Preliminary results suggest that MSeA leads to a decrease in outflow facility.The combination of MSeA-induced decreases in several indicators of HTM cell homeostasis (without adversely effects on cell viability at physiologically relevant doses) and decreases in outflow facility provide a possible mechanism for selenium-associated ocular hypertension.en_US
dc.typetexten_US
dc.typeElectronic Dissertationen_US
dc.subjectSeleniumen_US
dc.subjectTrabecular Meshworken_US
dc.subjectGlaucomaen_US
dc.subjectAngiogenesisen_US
dc.subjectExtracellular Matrixen_US
thesis.degree.namePhDen_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplinePharmacology & Toxicologyen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorStamer, W. Danielen_US
dc.contributor.advisorYool, Andrea J.en_US
dc.contributor.chairStamer, W. Danielen_US
dc.contributor.chairYool, Andrea J.en_US
dc.contributor.committeememberGandolfi, A. Jayen_US
dc.contributor.committeememberVaillancourt, Richard R.en_US
dc.contributor.committeememberStratton, Steven P.en_US
dc.identifier.proquest1402en_US
dc.identifier.oclc137355471en_US
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