The role of integrins in glaucoma

Filla, Mark S.; Faralli, Jennifer A.; Peotter, Jennifer L.; Peters, Donna M.

doi:10.1016/j.exer.2016.05.011

Cited by 53 publications

(50 citation statements)

References 154 publications

(232 reference statements)

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“…Peters and colleagues have published a number of sequential reports defining CLAN formation and structure (reviewed in (Filla et al, 2016; Gagen et al, 2014). CLANs are likely to be the same as the actin geodesic dome structures, first described by Lazarides and Burridge (Lazarides and Burridge, 1975), and may be a precursor structure to stress fibers.…”

Section: Cell Biologymentioning

confidence: 99%

Steroid-induced ocular hypertension/glaucoma: Focus on pharmacogenomics and implications for precision medicine

Fini

Schwartz

Gao

et al. 2017

Progress in Retinal and Eye Research

125

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Elevation of intraocular pressure (IOP) due to therapeutic use of glucocorticoids is called steroid-induced ocular hypertension (SIOH); this can lead to steroid-induced glaucoma (SIG). Glucocorticoids initiate signaling cascades ultimately affecting expression of hundreds of genes; this provides the potential for a highly personalized pharmacological response. Studies attempting to define genetic risk factors were undertaken early in the history of glucocorticoid use, however scientific tools available at that time were limited and progress stalled. In contrast, significant advances were made over the ensuing years in defining disease pathophysiology. As the genomics age emerged, it appeared the time was right to renew investigation into genetics. Pharmacogenomics is an unbiased discovery approach, not requiring an underlying hypothesis, and provides a way to pinpoint clinically significant genes and pathways that could not have been discovered any other way. Results of the first genome-wide association study to identify polymorphisms associated with SIOH, and follow-up on two novel genes linked to the disorder, GPR158 and HCG22, is discussed in the second half of the article. However, knowledge of genetic variants determining response to steroids in the eye also has value in its own right as a predictive and diagnostic tool. This article concludes with a discussion of how the Precision Medicine Initiative®, announced by U.S. President Obama in his 2015 State of the Union address, is beginning to touch the practice of ophthalmology. It is argued that SIOH/SIG may provide one of the next opportunities for effective application of precision medicine.

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Section: Cell Biologymentioning

confidence: 99%

Steroid-induced ocular hypertension/glaucoma: Focus on pharmacogenomics and implications for precision medicine

Fini

Schwartz

Gao

et al. 2017

Progress in Retinal and Eye Research

125

View full text Add to dashboard Cite

show abstract

“…Integrins influence cellular morphology, and facilitate processes such as cell migration and proliferation, wound repair, tissue organization, development, and host immune responses [24][25][26]. Integrins also participate in the pathogenesis of a wide range of diseases such as arthritis, cardiovascular disease, inflammation, microbial and parasitic infection, cancer, and glaucoma [27][28][29][30]. Integrins are heterodimeric transmembrane receptors containing one a subunit and one b subunit [25].…”

Section: Introductionmentioning

confidence: 99%

A cell adhesive peptide from tropoelastin promotes sequential cell attachment and spreading via distinct receptors

2017

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Tropoelastin is the dominant monomer that assembles to form elastin, which confers elasticity to vertebrate elastic tissues including skin, arteries, and lungs. Tropoelastin interacts with cells through cell surface receptors including integrins and glycosaminoglycans (GAGs). As the region 17-18 is recognized as a key region in cell attachment and spreading, we utilized C-terminal truncated tropoelastin constructs containing dissected sections of domain 18. We mapped a cell-interactive sequence of tropoelastin to domain 17 and the first six amino acids (aa) of domain 18. Further delineation identified a 21-residue sequence (Peptide 302-322) which promoted cell attachment and spreading indistinguishable from that to N18, a construct encompassing the full domains 17-18. Alanine substitution of the lysines at positions 11 and 14 in Peptide 302-322 effectively abolished cell binding. This reliance on lysines pointed to a role for GAGs, which was assessed by heparan sulfate inhibition, leading to 85.9 ± 4.2% decreased cell binding, while inhibition of integrins using ethylenediaminetetraacetic acid did not affect attachment. In contrast, selective antibody blocking of the integrin α family prevented cell spreading by 92.5 ± 8.9%. We propose a two-step mechanism by which cell interactions occur at this central region of tropoelastin: initially, cell adhesion is mediated by GAGs, which contact the lysine residues within the target sequence, and subsequently facilitate cell spreading modulated by integrins, specifically α β and α β . We conclude that this region comprises a tropoelastin-derived, cell-interactive sequence that independently mediates potent cell binding and spreading via sequential recognition of GAG and integrin cell surface receptors.

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“…In contrast to Piezo1 and TREK1 channels which are directly activated by pressure/stretch/indentation (89,90), the biophysical mechanism that activates TRPV4 channels in the presence of strain is not understood (81, 84, 91-93, 79, 80, 93, 95). It might involve β1 integrins, which bind the channel (5,30,87), are expressed in human and mouse TM (97,98), interact with ROCK (75), and contribute to IOP regulation and glaucoma (99,100). Interestingly, pretreatment with FAK or β1 integrin inhibitors suppressed sensitization of TRPV4 channels by mechanical stressors (Baratchi et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Mechanically induced cytoskeletal remodeling in trabecular meshwork cells requires TRPV4 - Rho signaling interactions

Lakk¹,

Križaj

2020

Preprint

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Intraocular pressure (IOP) is dynamically regulated by the trabecular meshwork (TM), a mechanosensitive tissue that protects the eye from injury through dynamic regulation of aqueous humor outflow from the anterior chamber of the eye. IOP-dependent increases in TM stiffness and contractility drive open angle glaucoma but the mechanotransduction mechanisms that regulate these processes remain poorly understood. We used fluorescence imaging and biochemical analyses to investigate cytoskeletal and focal adhesion remodeling in human TM cells stimulated with cyclic strain. The cells showed enhanced F-actin polymerization, increased number and size of focal adhesions, and activation of the Rho-associated protein kinase (ROCK). Stretch-induced activation of the small GTPase RhoA, and tyrosine phosphorylations of focal adhesion proteins paxillin, focal adhesion kinase (FAK), vinculin and zyxin were time-dependently inhibited by HC-067047, an antagonist of transient receptor potential vanilloid 4 (TRPV4) channels, and the ROCK inhibitor Y-27632. TRPV4 and ROCK activation were required for zyxin translocation and increase in the number/size of focal adhesions in stretched cells. Y-27632 blocked actin polymerization without affecting calcium influx induced by membrane stretch and the TRPV4 agonist GSK1016790A. These results reveal that mechanical tuning of TM cells requires parallel activation of TRPV4, integrins and ROCK, with chronic stress leading to sustained remodeling of the cytoskeleton and focal complexes.

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The role of integrins in glaucoma

Cited by 53 publications

References 154 publications

Steroid-induced ocular hypertension/glaucoma: Focus on pharmacogenomics and implications for precision medicine

Steroid-induced ocular hypertension/glaucoma: Focus on pharmacogenomics and implications for precision medicine

A cell adhesive peptide from tropoelastin promotes sequential cell attachment and spreading via distinct receptors

Mechanically induced cytoskeletal remodeling in trabecular meshwork cells requires TRPV4 - Rho signaling interactions

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