Animal Models Of Poag

Overview: Difficulty of modeling the human eye Limited access to appropriate biological materials, especially eye samples from affected donors at different stages of the POAG, is an impediment to the study of mechanisms underlying the disease. Because of the extreme difficulty in obtaining such diseased eyes from both patients and normal controls, animal models play a crucial role in investigating the biological pathway of disease development and in testing therapeutic strategies.

Different types of animal models for POAG have been found or created to mimic the optic nerve damage to resemble POAG phenotypes in humans. The greatest difficulty in constructing an animal model for POAG lies in the diversity of the anterior structures of the eye among different species (Tripathi and Tripathi, l972, l973). These structural differences include different iridocorneal angles or absence of specific quadrants from the TM. Nevertheless, within the limited areas in which interpretation of the data from a specific animal model parallels that in the human, various animals including the cow, dog, cat, horse, rabbit, chicken, and monkey can be used to observe POAG under various experimental conditions.

Animal models of POAG Various animal models for inducible glaucoma have been reported. Argon laser photocoagulation of the TM in rhesus monkeys results in sustained elevation of IOP and has been used extensively to study early damage to the optic nerve head (May et al., l997). Corticosteroids such as betamethasone and dexamethasone have been used to treat rabbits, dogs, and cats to develop ocular hypertension (Bonomi et al., l978). Steroid treatment generally produces progressive glaucoma, but this process is reversed after about two months after cessation of the steroid. Trabecular blockage caused by inflammation after a-chymotrypsin treatment also has been used to produce elevated IOP in rabbit and monkey eyes (Vareilles et al., l977). Some types of avian species (chicken, quail, and turkey) have been known to develop elevated IOP as a consequence of continuous exposure to light.

Mouse models of glaucoma Naturally occurring inherited animal glaucoma models are rare. However, extensive classification of IOP in mouse strains and molecular biological techniques to manipulate certain genes to produce transgenic or knockout/knockin mice recently have resulted in the development of a number of animal models with definitely known genetic causes for their disease (Chang et al., l999). As discussed earlier, four genes, myocilin (MYOC, TIGR), cytochrome P450lBl (CYPlBl), optineurin (OPTN), and WDR36, currently are associated with glaucoma. OPTN, mutations of which are responsible for l6.7% of families with hereditary human NTG, is homologous to an inhibitory regulatory subunit of the high molecular kinase complex for the phosphorylation of NF-kB. Some of its known functions include inhibition of the tumor necrosis factor-alpha pathway, interaction with transcription factor IIIA, and mediation of the Huntington and Rab8 interaction for regulation of membrane trafficking and cellular morphogenesis. OPTN is induced by TNF-a and binds to an inhibitor of TNF-a and the adenovirus E3-14.7 kDa protein. To determine the effects of human glaucoma mutations in a transgenic mouse system, mice over-expressing wild type OPTN, OPTN carrying the glaucoma associated mutation E50K, and OPTN with exon5 deleted were constructed. Although wild-type OPTN do not show any abnormalities and the exon 5 deleted construction was found to be lethal prenatally, mice transgenic for the E50K mutant OPTN show steep optic nerve cupping with rearrangement of supporting tissue and blood vessels 18 weeks after birth (see Figure 68.6). The RGC and astrocyte loss observed is similar to the end phase changes seen in human glaucoma patients. Understanding the mechanism underlying normal tension glaucoma in these transgenic mice will enhance our understanding of each step leading to optic nerve cupping and how to prevent it. Based on the success of the mouse model, use of larger animals such as transgenic rabbits or pigs, in which more precise measurement of IOP and trials of surgical procedures suitable for therapy in humans are possible are currently being investigated.

Other glaucoma mouse models have been made through genetic manipulation. Knockout and transgenic mouse models of myocilin were made to answer the question whether elevated expression of the myocilin

Figure 68.6 Histological section demonstrating excavation of the optic disc in an 18-week-old E50K mutant OPTN transgenic mouse.

protein can influence the IOP (Gould et al, 2004). Up to a fifteen-fold increase in myocilin expression failed to result in elevation of the IOP, any abnormality of retinal ganglion cells, or cupping of the optic nerve head. Mice lacking the cytochrome P450 1B1 (CYP1B1) gene were generated on B6 and 129X1/SvJ mouse stains (Libby et al., 2003). Both strains were affected by the CYP1B1 deficiency with focal angle abnormalities, but 129X1/SvJ albino strains lacking tyrosinase were more severely affected, suggesting the presence of tyrosinase as an important developmental molecule.

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