@article{1c474aad498345558be9b68460790e75,
title = "Inducible rodent models of glaucoma",
abstract = "Glaucoma is one of the leading causes of vision impairment worldwide. In order to further understand the molecular pathobiology of this disease and to develop better therapies, clinically relevant animal models are necessary. In recent years, both the rat and mouse have become popular models in glaucoma research. Key reasons are: many important biological similarities shared among rodent eyes and the human eye; development of improved methods to induce glaucoma and to evaluate glaucomatous damage; availability of genetic tools in the mouse; as well as the relatively low cost of rodent studies. Commonly studied rat and mouse glaucoma models include intraocular pressure (IOP)-dependent and pressure-independent models. The pressure-dependent models address the most important risk factor of elevated IOP, whereas the pressure-independent models assess “normal tension” glaucoma and other “non-IOP” related factors associated with glaucomatous damage. The current article provides descriptions of these models, their characterizations, specific techniques to induce glaucoma, mechanisms of injury, advantages, and limitations.",
keywords = "Animal model, Glaucoma, In vivo, Intraocular pressure, Pathogenesis, Rodent",
author = "Pang, {Iok Hou} and Clark, {Abbot F.}",
note = "Funding Information: Transcriptomics and proteomics comparisons between TM cells isolated from POAG donors and age-matched controls have shown increased expression of SFRP1 mRNA and protein in GTM cells (Wang et al., 2008a). SFRP1 is an antagonist of the Wnt signaling pathway. Wang and colleagues have shown that TM cells and TM tissues express Wnt agonists, Wnt receptors (FZLD), as well as Wnt antagonists (Wang et al., 2008a). This group also demonstrated that TM cells and tissues have a functional canonical Wnt β-catenin signaling pathway that regulates IOP (Mao et al., 2012; Wang et al., 2008a). Ad5.SFRP1 transduction of mouse eyes statistically elevated IOP and reduced aqueous outflow facility (Mao et al., 2012; Wang et al., 2008a), which was reversed by topical ocular administration of a GSK3β inhibitor, further supporting the role of the Wnt β-catenin pathway in regulating IOP. However, SFRP1 directly binds Wnt ligands and inhibits all 3 major Wnt signaling pathways (including the β-catenin pathway). In order to more directly determine which Wnt signaling pathway is involved in IOP regulation, we evaluated the IOP effects of the Wnt antagonist DKK1, which is specific for the Wnt β-catenin pathway. Ad5.DKK1 transduction of the TM in mice elevated IOP to the same extent as SFRP1 (Mao et al., 2012). This more conclusively demonstrates that the Wnt β-catenin signaling pathway regulates normal IOP, and perturbation of this signaling pathway causes OHT. Wnt stabilization of β-catenin leads to elevated cytosolic and nuclear levels of β-catenin (Mao et al., 2012). Nuclear β-catenin binds to TCF/LEF promoter regions, which mediate the expression of Wnt regulated genes. Cytoplasmic β-catenin binds to cadherin adhesion receptors and links them to the actin cytoskeleton. SFRP1 inhibition of Wnt signaling leads to the proteolytic degradation of β-catenin, thereby lowering both nuclear and cytoplasmic levels of β-catenin. This not only shuts down Wnt mediated gene expression, but also may interfere with cadherin junctions. The TM expresses a number of cadherins, including K-, OB-, and N-cadherins, and Wnt3a increased the expression of K-cadherin CDH, and this expression was decreased by SFRP1 (Webber et al., 2018). In order to determine whether SFRP1 suppression of K-cadherin expression was responsible for SFRP1-induced OHT, mouse eyes were transduced with Ad5.SFRP1 with or without concomitant transduction with Ad5.K-cadhein. Co-expression of K-cadherin along with SFRP1 significantly decreased SFRP1-induced OHT suggesting that at least part of the IOP elevating activity of SFRP1 is mediated by decreased expression of K-cadherin in the TM (Webber et al., 2018) (Fig. 12). In addition to using viral vectors to over-express specific glaucoma related transgenes, Ad5 also has been used to deliver Cre to the TM of conditional knockout (“floxed”) mice. This experimental approach does not require crossing a conditionally floxed mouse with a mouse strain having a tissue specific promoter driving Cre, which saves considerable time and expense. Also, no “TM specific promoter” has been identified to generate a specific TM Cre mouse line. Examples of this approach include Ad5.Cre delivery to the TM of Bambifl/fl mice (Hernandez et al., 2018). These mice have increased ECM expression in the TM and develop OHT due to a decreased outflow facility (Fig. 13), supporting the homeostatic role of TGFβ2/TLR4/BMP in the regulation of normal IOP. The role of the extracellular matrix cross-linking enzyme transglutaminase-2 (TGM2) in TGFβ2-induced OHT was confirmed using Ad5.Cre to knockdown TM TGM2 expression in Tgmfl/fl mice (Raychaudhuri et al., 2018). Knockdown of TGM2 expression in the TM significantly inhibited TGFβ2 OHT and reversed the decreased outflow facility. Publisher Copyright: {\textcopyright} 2019 Elsevier Ltd",
year = "2020",
month = mar,
doi = "10.1016/j.preteyeres.2019.100799",
language = "English",
volume = "75",
journal = "Progress in Retinal and Eye Research",
issn = "1350-9462",
publisher = "Elsevier Ltd",
}