The aqueous humor outflow pathways in glaucoma: A unifying concept of disease mechanisms and causative treatment

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

doi:10.1016/j.ejpb.2015.04.029

Cited by 138 publications

(158 citation statements)

References 70 publications

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“…The past decade has seen increasing interest in the biomechanical properties of the trabecular meshwork with relation to outflow resistance in ocular hypertension and glaucoma (reviewed and discussed in (Braunger et al, 2015; Stamer et al, 2015)). Organ stiffness can be evaluated using atomic force microscopy, which measures the indentation of the surface of tissue sections or whole mounts by a cantilever (Engler et al, 2007).…”

Section: Biomechanicsmentioning

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

105

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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: Biomechanicsmentioning

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

105

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show abstract

“…The elevation in IOP is generally attributed to a reduction in aqueous humor outflow from the trabecular meshwork as a result of excessive TM extracellular matrix (ECM) production and/or decreased turnover (Braunger et al, 2015; Keller et al, 2009; Pattabiraman and Toris, 2016). One protein that has been suggested as having a potentially significant role in the maintenance of ECM in the TM under both normal and glaucomatous conditions is fibronectin (Babizhayev and Brodskaya, 1989; Floyd et al, 1985; Hann et al, 2001)…”

Section: Introductionmentioning

confidence: 99%

Disruption of fibronectin matrix affects type IV collagen, fibrillin and laminin deposition into extracellular matrix of human trabecular meshwork (HTM) cells

Filla

Dimeo

Tong

et al. 2017

Experimental Eye Research

109

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Fibronectin fibrils are a major component of the extracellular matrix (ECM) of the trabecular meshwork (TM). They are a key mediator of the formation of the ECM which controls aqueous humor outflow and contributes to the pathogenesis of glaucoma. The purpose of this work was to determine if a fibronectin-binding peptide called FUD, derived from the Streptococcus pyogenes Functional Upstream Domain of the F1 adhesin protein, could be used to control fibronectin fibrillogenesis and hence ECM formation under conditions where its expression was induced by treatment with the glucocorticoid dexamethasone. FUD was very effective at preventing fibronectin fibrillogenesis in the presence or absence of steroid treatment as well as the removal of existing fibronectin fibrils. Disruption of fibronectin fibrillogenesis by FUD also disrupted the incorporation of type IV collagen, laminin and fibrillin into the ECM. The effect of FUD on these other protein matrices, however, was found to be dependent upon the maturity of the ECM when FUD was added. FUD effectively disrupted the incorporation of these other proteins into matrices when added to newly confluent cells that were forming a nascent ECM. In contrast, FUD had no effect on these other protein matrices if the cell cultures already possessed a preformed, mature ECM. Our studies indicate that FUD can be used to control fibronectin fibrillogenesis and that these fibrils play a role in regulating the assembly of other ECM protein into matrices involving type IV collagen, laminin, and fibrillin within the TM. This suggests that under in vivo conditions, FUD would selectively disrupt fibronectin fibrils and de novo assembly of other proteins into the ECM. Finally, our studies suggest that targeting fibronectin fibril assembly may be a viable treatment for POAG as well as other glaucomas involving excessive or abnormal matrix deposition of the ECM.

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“…Most anterior segment molecular theories for elevated IOP involve some pathologic agent (TGF-beta, CTGF, etc.) in the aqueous humor (Braunger et al 2015). Since elevation of outflow resistance in glaucoma is not absolute (meaning zero outflow), some flow still continues past the TM in the diseased state into the distal outflow pathway potentially negatively impacting these regions as well.…”

Section: Distal Outflowmentioning

confidence: 99%

Corticosteroids and Anti-Complement Therapy in Retinal Diseases

Narayanan

Kuppermann

2016

Handbook of Experimental Pharmacology

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The aqueous humor outflow pathways in glaucoma: A unifying concept of disease mechanisms and causative treatment

Cited by 138 publications

References 70 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

Disruption of fibronectin matrix affects type IV collagen, fibrillin and laminin deposition into extracellular matrix of human trabecular meshwork (HTM) cells

Corticosteroids and Anti-Complement Therapy in Retinal Diseases

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