Reduced Corneal Thickness and Enlarged Anterior Chamber in a Novel ColVIIIa2<sup>G257D</sup>Mutant Mouse

Puk, Oliver; Dalke, Claudia; Calzada‐Wack, Julia; Ahmad, Nafees; Klaften, Matthias; Wagner, Sibylle; Angelis, Martin Hrabé de; Graw, Jochen

doi:10.1167/iovs.09-3550

Cited by 25 publications

(17 citation statements)

References 48 publications

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“…These mice were subsequently found to have progressive axon loss (Mabuchi et al, 2004). Aca23 mutant mice were found to contain a G770A point mutation in the COL8A2 gene (Puk et al, 2009). The mutation was mapped to a non-synonymous change, G257D, located at the critical glycine residue of the triplet, Gly-X-Y.…”

Section: Ecm Manipulations That Alter Iop In Animal Modelsmentioning

confidence: 99%

Extracellular matrix in the trabecular meshwork: Intraocular pressure regulation and dysregulation in glaucoma

Vranka

Kelley

Acott

et al. 2015

Experimental Eye Research

306

291

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The trabecular meshwork (TM) is located in the anterior segment of the eye and is responsible for regulating the outflow of aqueous humor. Increased resistance to aqueous outflow causes intraocular pressure to increase, which is the primary risk factor for glaucoma. TM cells reside on a series of fenestrated beams and sheets through which the aqueous humor flows to exit the anterior chamber via Schlemm’s canal. The outer trabecular cells are phagocytic and are thought to function as a pre-filter. However, most of the outflow resistance is thought to be from the extracellular matrix (ECM) of the juxtacanalicular region, the deepest portion of the TM, and from the inner wall basement membrane of Schlemm’s canal. It is becoming increasingly evident that the extracellular milieu is important in maintaining the integrity of the TM. Not only have ultrastructural changes been observed in the ECM of the TM in glaucoma, and a significant number of mutations in ECM genes are known to be associated with glaucoma, but the stiffness of glaucomatous TM appears to be greater than that of normal tissue. Additionally, TGFβ2 has been found to be elevated in the aqueous humor of glaucoma patients and is assumed to be involved in ECM changes deep with the juxtacanalicular region of the TM. This review summarizes the current literature on trabecular ECM as well as the development and function of the TM. Animal models and organ culture models targeting specific ECM molecules to investigate the mechanisms of glaucoma are described. Finally, the growing number of mutations that have been identified in ECM genes and genes that modulate ECM in humans with glaucoma are documented.

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Section: Ecm Manipulations That Alter Iop In Animal Modelsmentioning

confidence: 99%

Extracellular matrix in the trabecular meshwork: Intraocular pressure regulation and dysregulation in glaucoma

Vranka

Kelley

Acott

et al. 2015

Experimental Eye Research

306

291

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“…37 Collagen VIII is suggested to be partially responsible for the correct assembly of Descemet's membrane to ensure corneal stability. 38 Endothelial cells contain numerous mitochondria and the Golgi complex, indicating that they are metabolically active and secretory. 39 This is related to the Na þ / K þ -ATP pump and Descemet's membrane secretion, respectively.…”

Section: Corneal Endothelium Physiologymentioning

confidence: 99%

Corneal endothelium: developmental strategies for regeneration

Zavala

Jaime

Barrientos

et al. 2013

Eye

111

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The main treatment available for restoration of the corneal endothelium is keratoplasty. This procedure is faced with several difficulties, including the shortage of donor tissue, postsurgical complications associated with the use of drugs to prevent immune rejection, and a significant increase in the occurrence of glaucoma. Recently, surgical procedures such as Descemet's stripping endothelial keratoplasty have focused on the transplant of corneal endothelium, yielding better visual results but still facing the need for donor tissue. The emergent strategies in the field of cell biology and tissue cultivation of corneal endothelial cells aim at the production of transplantable endothelial cell sheets. Cell therapy focuses on the culture of corneal endothelial cells retrieved from the donor, in the donor's cornea, followed by transplantation into the recipient. Recently, research has focused on overcoming the challenge of harvesting human corneal endothelial cells and the generation of new biomembranes to be used as cell scaffolds in surgical procedures. The use of corneal endothelial precursors from the peripheral cornea has also demonstrated to be effective and represents a valuable tool for reducing the risk of rejection in allogeneic transplants. Several animal model reports also support the use of adult stem cells as therapy for corneal diseases. Current results represent important progresses in the development of new strategies based on alternative sources of tissue for the treatment of corneal endotheliopathies. Different databases were used to search literature: PubMed, Google Books, MD Consult, Google Scholar, Gene Cards, and NCBI Books. The main search terms used were: 'cornea AND embryology AND transcription factors', 'human endothelial keratoplasty AND risk factors', '(cornea OR corneal) AND (endothelium OR endothelial) AND cell culture', 'mesenchymal stem cells AND cell therapy', 'mesenchymal stem cells AND cornea', and 'stem cells AND (cornea OR corneal) AND (endothelial OR endothelium)'.

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“…Three strains of mice at 3 to 4 months of age were studied in one or both eyes: 9 C57BL/6 mice (B6 from Jackson Laboratories, Bar Harbor, ME, USA), 9 CD1 mice (Charles River Laboratories, Wilmington, MA, USA), and 10 Aca23 mutant mice (base strain B6), previously described. 30 In addition, six CD1 mice at 15 months of age were studied. The word ''strain'' is used in this report generally to indicate a particular type of mouse, not in the sense of mechanical stress-strain, except where specifically discussing biomechanical behavior.…”

Section: Animalsmentioning

confidence: 99%

“…1,12,20,29 Chronically elevated IOP in mice leads to decreases in nonfibrillar scleral elements, alterations in collagen lamellar orientation, a decrease in collagen fibril diameter, and increased cell division with a transition to the myofibroblast phenotype in scleral fibroblasts (Oglesby EN, unpublished observations, Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc. www.iovs.org j ISSN: 1552-5783 2013). 16 Aca23 mice (mice of B6 background that are homozygous for mutation in collagen 8a2) are significantly protected against injury from experimental glaucoma, 30,31 while CD1 mice are considerably more susceptible to damage than B6 mice 32 and differ in important features of scleral anatomy and response. 9,33 Experimental glaucoma in mice increases axial length and width by 6% to 10%, with thinning of the peripapillary sclera and increased scleral stiffness in mechanical inflation testing.…”

mentioning

confidence: 99%

Scleral Permeability Varies by Mouse Strain and Is Decreased by Chronic Experimental Glaucoma

Pease

Oglesby

Cone-Kimball

et al. 2014

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. To determine differences in scleral permeability, as measured by diffusion of macromolecules, by using fluorescence recovery after photobleaching (FRAP), with reference to differences by mouse strain, scleral region, and the effect of experimental glaucoma.METHODS. In three mouse strains (B6, CD1, and B6 mice with mutation in collagen 8a2[Aca23]), we used FRAP to measure the diffusion of fluorescein isothiocyanate-dextran, molecular weight 40 kDa, into a photobleached zone of sclera. Scleral regions near the optic nerve head (peripapillary) and two successively more anterior regions were compared. Sclera from mouse eyes subjected to chronically elevated intraocular pressure after bead injection into the anterior chamber were compared to fellow eye controls. FRAP data were compared against estimated retinal ganglion cell axon loss in glaucomatous eyes.RESULTS. Diffusion rates of dextran molecules in the sclera were significantly greater in Aca23 and B6 mice than in CD1 mice in a multivariate model adjusted for region and axial length (P < 0.0001). Dextran diffusion significantly decreased in glaucomatous eyes, and the decline increased with greater axon loss (P ¼ 0.0003, multivariable model). Peripapillary scleral permeability was higher in CD1 than B6 and Aca23 mice (P < 0.05, multivariable model, adjusted by Bonferroni). CONCLUSIONS.Measurement of the diffusion rates of dextran molecules in the sclera showed that glaucoma leads to decreased scleral permeability in all three mouse strains tested. Among mouse strains tested, those that were more susceptible to glaucomatous loss of retinal ganglion cells had a lower scleral permeability at baseline.Keywords: glaucoma, mouse, experimental model, sclera, diffusion, permeability, photobleaching, dextran G laucoma is the second leading cause of world blindness and its principal risk factors include the effect of intraocular pressure (IOP) acting to decrease the number of retinal ganglion cells (RGCs). Intraocular pressure is a mechanical load that generates stress and strain in the sclera, which are magnified at the optic nerve head (ONH). The largest mechanical strains have been measured in in vitro inflation experiments in the peripapillary region, immediately adjacent to the ONH.1 The sclera acts on the ONH, where axons of RGCs pass out of the eye, and suffers damage related to the effects of IOP.2,3 Thus, the behavior of the sclera is highly relevant to glaucoma injury and its study may be useful in improved diagnosis as well as new therapeutic avenues.The sclera comprises three-quarters of the human ocular circumference and is 75% to 90% collagen, with additional elastin fibrils and proteoglycans. 4,5 The scleral proteoglycans include heparin sulfate, chondroitin sulfate, dermatan sulfate, keratan sulfate, hyaluronan, aggrecan, and several small leucinerich proteoglycans.6,7 These may have important functional significance for the mechanical responses of the sclera. 8 Scleral thickness is greatest at the peripapillary zone, followed by the limbus, and is...

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Reduced Corneal Thickness and Enlarged Anterior Chamber in a Novel ColVIIIa2^G257DMutant Mouse

Cited by 25 publications

References 48 publications

Extracellular matrix in the trabecular meshwork: Intraocular pressure regulation and dysregulation in glaucoma

Extracellular matrix in the trabecular meshwork: Intraocular pressure regulation and dysregulation in glaucoma

Corneal endothelium: developmental strategies for regeneration

Scleral Permeability Varies by Mouse Strain and Is Decreased by Chronic Experimental Glaucoma

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Reduced Corneal Thickness and Enlarged Anterior Chamber in a Novel ColVIIIa2G257DMutant Mouse

Cited by 25 publications

References 48 publications

Extracellular matrix in the trabecular meshwork: Intraocular pressure regulation and dysregulation in glaucoma

Extracellular matrix in the trabecular meshwork: Intraocular pressure regulation and dysregulation in glaucoma

Corneal endothelium: developmental strategies for regeneration

Scleral Permeability Varies by Mouse Strain and Is Decreased by Chronic Experimental Glaucoma

Contact Info

Product

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Reduced Corneal Thickness and Enlarged Anterior Chamber in a Novel ColVIIIa2^G257DMutant Mouse