Intraocular Pressure and the Mechanisms Involved in Resistance of the Aqueous Humor Flow in the Trabecular Meshwork Outflow Pathways

Tamm, Ernst R.; Braunger, Barbara M.; Fuchshofer, Rudolf

doi:10.1016/bs.pmbts.2015.06.007

Cited by 115 publications

(103 citation statements)

References 42 publications

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“…A contributor to TM dysfunction is TM cell death, 24,43 which can be brought about by the aggregation of mutant myocilin. 44 Nonsynonymous mutations in myocilin, localized to its olfactomedin domain, result in non-native tertiary structures, which promote facile aggregation and leads to TM cell death.…”

Section: Primary Open Angle Glaucoma and Grp94-selective Inhibitionmentioning

confidence: 99%

Development of Glucose Regulated Protein 94-Selective Inhibitors Based on the BnIm and Radamide Scaffold

et al. 2016

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Glucose regulated protein 94 (Grp94) is the endoplasmic reticulum resident of the heat shock protein 90 kDa (Hsp90) family of molecular chaperones. Grp94 associates with many proteins involved in cell adhesion and signaling, including integrins, Toll-like receptors, immunoglobulins, and mutant myocilin. Grp94 has been implicated as a target for several therapeutic areas including glaucoma, cancer metastasis, and multiple myeloma. While 85% identical to other Hsp90 isoforms, the N-terminal ATP-binding site of Grp94 possesses a unique hydrophobic pocket that was used to design isoform-selective inhibitors. Incorporation of a cis-amide bioisostere into the radamide scaffold led to development of the original Grp94-selective inhibitor, BnIm. Structure–activity relationship studies have now been performed on the aryl side chain of BnIm, which resulted in improved analogues that exhibit better potency and selectivity for Grp94. These analogues also manifest superior antimigratory activity in a metastasis model as well as enhanced mutant myocilin degradation in a glaucoma model compared to BnIm.

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Section: Primary Open Angle Glaucoma and Grp94-selective Inhibitionmentioning

confidence: 99%

Development of Glucose Regulated Protein 94-Selective Inhibitors Based on the BnIm and Radamide Scaffold

et al. 2016

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“…In addition, the trabecular meshwork is considered to be involved in the regulation of IOP, due to observations that glaucoma trabecular meshwork cells undergo increased rates of apoptosis in a high IOP state (40). Nrf2 is a key transcription factor in the regulation of antioxidant and Phase II detoxification gene expression, and is activated by oxidative stress and the presence of electrophiles.…”

Section: Discussionmentioning

confidence: 99%

Role of nuclear factor (erythroid-derived 2)-like 2 in the age-resistant properties of the glaucoma trabecular meshwork

Cheng¹,

Liang²,

Qi³

2017

Experimental and Therapeutic Medicine

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Abstract. Glaucoma is a major cause of irreversible blindness. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) regulates the expression of numerous antioxidants within cells and is therefore a focus of current ophthalmic research. To determine the roles of Nrf2 in mediating the glaucoma trabecular meshwork (GTM), the present study evaluated the levels of Nrf2 expression in GTM and human trabecular meshwork (HTM) cells by reverse-transcription-quantitative polymerase chain reaction and western blot analysis. It was principally observed that Nrf2 expression was downregulated in GTM cells. In addition, to determine the influence of Nrf2 on the apoptosis and proliferation of GTM and HTM cells, transfection assays and western blotting were performed to evaluate the expression of apoptosis-related proteins. The results of the current study indicated that Nrf2 may promote viability and reduce apoptosis in GTM and HTM cells. Collectively, these data suggest that Nrf2 may be a novel therapeutic target to treat glaucoma.

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“…The TM tissue can be divided into three regions: the uveal meshwork, the corneoscleral meshwork and the JCT, where Schlemm’s canal (SC) inner wall cells interact with JCT cells. (Stamer and Acott, 2012; Tamm et al, 2015) Here in the JCT region is where resistance to outflow is generated and IOP is determined. (Grant, 1963; Tamm et al, 2015) Increased resistance in the JCT is responsible for ocular hypertension frequently observed in POAG.…”

Section: Juxtacanalicular Tissue Cellsmentioning

confidence: 99%

“…(Stamer and Acott, 2012; Tamm et al, 2015) Here in the JCT region is where resistance to outflow is generated and IOP is determined. (Grant, 1963; Tamm et al, 2015) Increased resistance in the JCT is responsible for ocular hypertension frequently observed in POAG. (Grant, 1951) While resistance generation is complicated, the primary contributors are the contraction status of JCT cells, ECM abundance/content of the JCT and permeability of the inner wall of SC.…”

Section: Juxtacanalicular Tissue Cellsmentioning

confidence: 99%

“…Moreover, responsiveness and susceptibility of both cribriform tissues to glaucoma may be in the context of genetic background and/or factors found up-regulated in different parts of the eye, such as reactive oxygen species or transforming growth factor-beta-2 (TGF-beta2). (Agarwal et al, 2015; Awai-Kasaoka et al, 2013; McElnea et al, 2011; O’Reilly et al, 2011; Pena et al, 1999; Tamm et al, 2015). …”

Section: Introductionmentioning

confidence: 99%

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Life under pressure: The role of ocular cribriform cells in preventing glaucoma

Paula

O’Brien

Stamer

2016

Experimental Eye Research

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Primary open-angle glaucoma is a multifactorial blinding disease often impacting the two pressure-sensitive regions of the eye: the conventional outflow pathway and the optic nerve head (ONH). The connective tissues that span these two openings in the globe are the trabecular meshwork of the conventional outflow pathway and the lamina cribrosa of the ONH. Resident cribiform cells of these two regions are responsible for actively remodeling and maintaining their connective tissues. In glaucoma, aberrant maintenance of the juxtacanalicular tissues (JCT) of the conventional outflow pathway results in ocular hypertension and pathological remodeling of the lamina cribrosa results in ONH cupping, damaging retinal ganglion cell axons. Interestingly, cells cultured from the lamina cribrosa and the JCT of the trabecular meshwork have similarities regarding gene expression, protein production, plus cellular responses to growth factors and mechanical stimuli. This review compares and contrasts the current knowledge of these two cell types, whose health is critical for protecting the eye from glaucomatous changes. In response to pressure gradients across their respective cribiform tissues, the goal is to better understand and differentiate healthy from pathological behavior of these two cell types.

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Intraocular Pressure and the Mechanisms Involved in Resistance of the Aqueous Humor Flow in the Trabecular Meshwork Outflow Pathways

Cited by 115 publications

References 42 publications

Development of Glucose Regulated Protein 94-Selective Inhibitors Based on the BnIm and Radamide Scaffold

Development of Glucose Regulated Protein 94-Selective Inhibitors Based on the BnIm and Radamide Scaffold

Role of nuclear factor (erythroid-derived 2)-like 2 in the age-resistant properties of the glaucoma trabecular meshwork

Life under pressure: The role of ocular cribriform cells in preventing glaucoma

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