Abstract
Members of the transforming growth factor beta (TGFβ) cytokine family have long been associated with affecting several cellular functions, including cell proliferation, differentiation and extracellular matrix (ECM) turnover. Of particular interest to this work, TGFβ2 has been linked to most types of glaucomas as a potential fibrotic agent that can cause elevation of intraocular pressure (IOP). Given that the trabecular meshwork (TM) provides most of aqueous humor outflow resistance in the eye, an in vitro bioengineered human TM (HTM) model has been created and validated by analyzing effects of TGFβ2 on transcellular pressure changes and outflow facility. These changes were correlated with several biological alterations induced by this cytokine, including ECM production and overexpression of HTM-marker myocillin. Furthermore, this TM model has been used to extend current knowledge of gene expression of cytokines involved in TGFβ-induced ECM turnover over time. In particular, the ability for a ROCK-inhibitor to diminish the effect of TGFβ on TM was demonstrated. This work supports the notion that anti-fibrotic activities of ROCK-inhibitors could counteract the elevation of IOP and increased strain observed in glaucomatous TM.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Actins / genetics
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Actins / metabolism
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Amides / pharmacology*
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Animals
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Cytoskeletal Proteins / genetics
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Cytoskeletal Proteins / metabolism
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Epoxy Compounds / chemistry
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Eye Proteins / genetics
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Eye Proteins / metabolism
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Gene Expression Regulation
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Glycoproteins / genetics
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Glycoproteins / metabolism
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Humans
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Intraocular Pressure / physiology
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Models, Biological
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Perfusion
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Polymers / chemistry
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Pyridines / pharmacology*
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Signal Transduction
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Tissue Culture Techniques
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Tissue Engineering / methods*
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Tissue Scaffolds*
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Trabecular Meshwork / cytology
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Trabecular Meshwork / drug effects*
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Trabecular Meshwork / metabolism
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Transforming Growth Factor beta2 / antagonists & inhibitors
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Transforming Growth Factor beta2 / pharmacology*
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alpha-Crystallin B Chain / genetics
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alpha-Crystallin B Chain / metabolism
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rho-Associated Kinases / antagonists & inhibitors*
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rho-Associated Kinases / genetics
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rho-Associated Kinases / metabolism
Substances
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ACTA2 protein, human
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Actins
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Amides
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CRYAB protein, human
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Cytoskeletal Proteins
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Epoxy Compounds
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Eye Proteins
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Glycoproteins
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Polymers
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Pyridines
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SU-8 compound
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Transforming Growth Factor beta2
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alpha-Crystallin B Chain
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trabecular meshwork-induced glucocorticoid response protein
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Y 27632
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ROCK1 protein, human
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rho-Associated Kinases