Animal Models of GlaucomaS I Tomarev, National Institutes of Health, Bethesda, MD, USA

Published by Elsevier Ltd.

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Glossary

BAC – Bacterial artificial chromosome. It is a DNA

construct based on a functional fertility plasmid, used

for cloning in bacteria. The bacterial artificial

chromosome’s usual insert size is 150–350 kbp.

BAX – Proapoptotic BCL2-associated X protein.

BCL2 is an integral outer mitochondrial membrane

protein that blocks the apoptotic death of some cells.

Retrobulbar space – The area located behind the

globe of the eye.

Synechia – An eye condition where the iris adheres

to either the cornea (anterior synechia) or the lens

(posterior synechia).

Tonometry – The procedure to determine the

intraocular pressure.

TUNEL – Terminal deoxynucleotidyl transferase-

mediated deoxyuridine triphosphate nick end

labeling for detection of DNA fragmentation resulting

from apoptotic programmed cell death.

Glaucoma is a complex disease, the initiation and pro-gression of which involves interactions between differentparts of the eye and brain. It is difficult to perform experi-ments directed toward elucidating pathogenic molecularmechanisms and potential treatments for glaucoma inhuman subjects and, as a rule, only postmortem materialcan be used for biochemical analysis. Experiments in cellculture or organ culture systems may only partially repro-duce the complexity of the natural ocular environment. Itis now well recognized that animal models may provide avery useful tool for understanding the underlying molec-ular mechanisms involved in glaucoma and for identifyingnew genetic components of the disease, including bothcausative and modifier genes. In addition, appropriateanimal models are used to develop and test new regimentsof glaucoma treatment as a prerequisite for clinical trialsin humans. A number of animal models of glaucoma havebeen developed over the years. Since elevated intraocularpressure (IOP) is the most important risk factor in glau-coma, most of the animal models of glaucoma are basedon elevation of IOP by surgical procedures or by geneticmanipulations. Several models used to study death of theretinal ganglion cells (RGCs) include optic nerve crush ortransaction, intravitreal injection of excitory amino acids(glutamate and N-methyl-D-aspartic acid (NMDA)), orretinal ischemia. Although these are not true glaucoma

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models, they allow the comparison of processes leadingto RGC death induced by different initial insults. Suchcomparative analysis may lead to the identification ofchanges that are specific to glaucoma versus changesthat are involved in more general RGC dysfunction.While none of the existing animal models is perfect,some of the existing models have been successfully usedto uncover important features of glaucoma pathology inhumans. Several factors should be considered in selectinga particular animal model of glaucoma for experimenta-tion: (1) the similarity of the model visual system to thehuman eye; (2) the similarity in the time course of patho-logical changes in the model and human eyes; (3) abilityto apply genetic manipulations; (4) training necessary toproduce affected animals; (5) the size of the eye; (6) avail-ability and difficulties of methods of analysis; (7) availabil-ity of animals; and (8) cost. This article briefly describesavailable animal models of glaucoma with emphasis onthe strengths and weaknesses of each model.

Mammalian Models

Primate Models of Glaucoma

Monkey and human eyes are very similar both anatomi-cally and functionally, making monkey models very attrac-tive to study different eye pathologies including glaucoma.IOP in monkeys is measured using the same equipmentthat is used to measure IOP in humans. Moreover, tonom-etry and visual-field analysis can be performed in con-scious, trained monkeys. This is an important factor sinceit is well documented that general anesthesia that is neces-sary to measure IOP in most other animal models results inrapid ocular hypotension. The main disadvantage of mon-keymodels is that experimentswithmonkeys are expensiveand require a highly skilled team of investigators. More-over, large numbers of animals are required to assess effectsof elevated IOP on the optic nerve head (ONH) and retinabecause of genetic variations between animals.

Several approaches have been used to develop pressure-induced glaucoma models in nonhuman primates. Themost common method of IOP elevation in the monkeywas originally developed more than 30 years ago andinvolves circumferential laser photocoagulation treatmentof the trabecular meshwork. Several laser sessions are nor-mally required to produce a sustained elevation of IOP. Inthe treated eyes, IOP rises several days after the lasertreatment, normally to between 25 and 60 mmHg, andmay last for more than a year. Other methods that have

Animal Models of Glaucoma 107

been used to produce elevated IOP elevation in monkeysare less consistent than laser coagulation. They includeinjection of ghost red cells, latexmicrospheres, cross-linkedpolyacrylamide gels, or enzymes into the anterior chamberor application of topical steroids. A non-IOP-related mon-keymodel of glaucoma involves the deliveryof endothelin-1 to the retrobulbar space through osmotic pump for6–12 months; this induces ischemia and leads to the pref-erential loss of large RGC axons. Ischemia-induced focalaxonal loss is similar to human glaucoma and this modelmay reproduce some aspects of normal tension glaucoma.

A number of important observations have been madeusing themonkey photocoagulationmodel. Apoptosis as theprimary mechanism of glaucomatous RGC death was firstdemonstrated in this model before later being confirmed inother models and in human glaucoma. Multifocal electro-retinogram (ERG) techniques were used in monkeys todemonstrate that not only RGCs but also cells in the innerand outer nuclear layers are damaged in advanced glau-coma. The monkey glaucoma model has been successfullyused to study changes in retinal gene expression patternsafter the induction of ocular hypertension. It is also beingused to efficiently test new drugs and techniques to reduceIOP. For instance, recombinant adenoviral delivery of thehuman p21WAF-1/cip-1 gene to cause cell cycle arrest beforefiltration surgery in ocular hypertensive monkey eyes hasshown a beneficial effect in long-term control of IOP.

Rodent Models of Glaucoma

Several rodent models of glaucoma have been developedover the last 20 years and newmodels are at different stagesof development in several laboratories. These models haveproven useful because the drainage structures of the rodenteye are similar to those in humans. Their utility wasenhanced further by the development of new methods tomeasure IOP and analyze glaucomatous changes in thesesmall eyes. Rodent models, and especially mouse models,are relatively cheap and allow extensive genetic manipula-tions. Rodent models are preferredwhen a significant num-ber of animals are required to conduct genetic screens or totest different drugs and agents for neuroprotective or IOP-lowering effects. One of the main disadvantages of rodentmodels is that there are anatomical differences betweenrodent and human eyes, including the arterial blood supplyto the ONH and the absence of a well-developed, collage-nous lamina cribrosa. These variations, aswell as differencesin general physiology, may explain why expression of cer-tain genes in mouse and human eyes (e.g., mutated myoci-lin) have differential effects.

Rat Models

Rats are easy to handle. The relatively large size oftheir eyes allows multiple noninvasive IOP measurements

in awake trained animals with commercially availableequipment. The TonoPen was the instrument of choicefor IOP measurements for many years but has recentlybeen superseded by an induction/impact tonometer,marketed as the TonoLab rebound tonometer. Thisinstrument is easy to operate and can be used in bothrats and mice.

Several rat models of pressure-induced glaucoma havebeen developed over the last 15 years. IOP elevation in therat eye may be achieved by injection of hypertonic salinesolution into the episcleral vein that leads to sclerosis of theaqueous humor outflow pathway. Sustained IOP elevationoccurs 7–10 days after injection inmost but not all rats. Thesaline injection generally produces a range of IOPelevationin different animals from a very minimal rise to twofoldincrease over IOP in control eyes, which can remain ele-vated for up to several months. Cauterization of two ormore of the four large episcleral veins is another method ofIOP elevation. In this model, IOP elevation occurs veryquickly and there are some indications that this procedureimpedes blood outflow from the globe and leads to ische-mia. Reports indicate that IOP elevation may last fromseveral weeks to several months without requiring retreat-ment. IOP increase can be also achieved by laser photoco-agulation of the trabecular meshwork with or withoutinjection of Indian ink into anterior chamber. Intracameralinjection of hyaluronic acid or latex microspheres isanother method of IOP elevation in rats. However, therepeated weekly injections required by this method mayproduce undesirable effects and are labor consuming. Top-ical application of dexamethasone for 4 weeks may also beused to induce ocular hypertension. These methods ofchronic IOP elevation in rats are accompanied by deathof the RGCs by apoptosis, optic nerve degeneration, andONH remodeling similar to those observed in glaucoma inhumans. Acute ocular hypertension, on the other hand,may be produced in rats by cannulation of the anteriorchamber with a needle attached to a saline reservoir.Although such treatment leads to retinal ischemic injury,it has been suggested that this model mimics acute angle-closure glaucoma in humans.

A mutant rat strain with a unilateral or bilateral globeenlargement and IOPs that range from 25 to 45 mmHghave been described. In this strain, cupping of the ONHas well as reduction in the number of RGCs progresswith age. Unfortunately, this strain was obtained fromthe Royal College of Surgeons colony that has a mutationin the receptor tyrosine kinase gene, leading to degenera-tion of the photoreceptors. This drastically limits theutility of this strain to study phenomena that are specificto glaucoma and not confounded by other neurodegener-ative processes.

Rat models of glaucoma have been used to study effectsof elevated IOP on the ERG, changes in the gene expres-sion patterns in the retina, RGCs and optic nerve, and

108 Animal Models of Glaucoma

changes in the protein spectrum of the retina. Rat modelsalso are often used to study neuroprotection. For instance,the hypertonic saline model was used to demonstrate forthe first time that agents targeting multiple phases of theamyloid-b pathway provide a therapeutic avenue in glau-coma management.

Mouse Models

Mouse models of glaucoma recently have become verypopular. Although most mouse models of glaucoma arebased on the elevation of IOP, information about IOP isessential even for the models that do not include experi-mental IOP manipulation. The mouse eye is much smallerthan the human eye, and devices designed for tonometryin humans do not produce reliable data in the mouse.Thus, new methods to measure IOP in mice have beendeveloped and, as a result, the development and accep-tance of mouse models of glaucoma have been acceler-ated. Currently, several invasive and noninvasive methodsof IOP measurements in mice exist. The oldest methodremains as one of the most reliable and accurate methodsand does not depend upon the mechanical properties ofthe cornea. It involves the insertion of a glass microneedleconnected to a pressure transducer into anterior chamberof the eye. However, this procedure cannot be performedtoo frequently in the same eye, as adequate time isrequired for corneal wound healing. In addition, cannula-tion tonometry is technically difficult and training isrequired to develop sufficient expertise to obtain reliableIOP readings. Cannulation tonometry was used to dem-onstrate that common mouse strains exhibit differentaverage IOPs in the range between 10 and 20 mmHg.Other methods of IOP measurements in mice were laterdeveloped including noninvasive techniques (TonoLabtonometer). Noninvasive techniques allow multiple IOPmeasurements within short periods of time without exten-sive training.

Pressure-induced mouse models

Surgical approaches similar to those that were used toproduce elevated IOP in rats have also been developed inmice. Significant elevation of IOP in the C57BL/6J mouseeye is accomplished by combined injection of indocyaninegreen dye into the anterior chamber and diode lasertreatment of the trabecular meshwork and episcleralvein region. IOP in operated eyes is significantly elevated10 days after the surgery but returns back to normal60 days after the procedure. Histological analysis of thetreated eyes 65 days after the surgery revealed develop-ment of anterior synechia, loss of RGCs, thinning of allretinal layers, and damage to the optic nerve structureswithout evidence of prominent cupping. A reduction inthe function of all retinal layers, as assessed by ERGstudies, indicates that this model produces more dramatic

changes in the retina compared to glaucoma in humans.Elevation of IOP may also be induced by argon laserphotocoagulation of the episcleral and limbal veins inC57BL/6J mouse eyes or by cauterization of three episcl-eral veins in CD1 mouse eyes. In one study, mean IOP inthe eyes that underwent laser treatment was about 1.5 timeshigher than in control eyes for 4 weeks. RGC loss was22.4 � 7.5% at 4 weeks after treatment with the majorityof terminal deoxynucleotidyl transferasemediateddeoxyur-idine triphosphate (dUTP) nick end labeling (TUNEL)-positive apoptotic cells detected in the peripheral areas ofthe retina. Episcleral vein cauterization produced a maxi-mum IOP elevation within 2–9 days after the procedure,which decreased progressively after that to baseline values inthe following 24–33 days. This was associated with a 20%decline in the number of RGCs 2 weeks after the surgery.

The DBA/2J strain has become a popular mousemodel of secondary-angle-closure glaucoma and is oneof the best-characterized mouse models of glaucoma ingeneral. DBA/2J mice have mutations in two genes, Tyrp1and Gpnmb, which lead to pigment dispersion, iris transil-lumination, iris atrophy, and anterior synechia. IOP iselevated in most mice by the age of 9 months. IOP eleva-tion was accompanied by the death of the RGCs, opticnerve atrophy, and optic nerve cupping. Although nogroup of the RGCs appears especially vulnerable or resis-tant to degeneration, fan-shaped sectors of cell death andsurvival radiating from the ONH have been detected. Ithas been suggested that axon damage at the ONH mightbe a primary lesion in this model. Several importantobservations have been made using DBA/2J model. Itwas shown that proapoptotic protein BAX is required forRGC death but not for RGC axon degeneration in thismodel of glaucoma, suggesting that BAX may be a candi-date human glaucoma susceptibility gene. Unexpectedly,high dose of g-irradiation accompanied with syngenicbone marrow transfer protected RGCs in DBA/2J. Simi-lar to the results obtained with rat and monkey models,genes involved in the glial activation and immune responseare activated inDBA/2J retina as shown by array hybridiza-tion. Complement component C1q is upregulated in theretina in several animal models of glaucoma and humanglaucoma with timing, suggesting that complement activa-tion plays a significant role in glaucoma pathogenesis.Recent data suggest that complement proteins opsonizecentral nervous system synapses during a distinct windowof postnatal development and that the complement proteinsC1q and C3 are required for synapse elimination in thedeveloping retinogeniculate pathway. InDBA/2Jmice, C1qrelocalizes to adult retinal synapses at an early stage ofglaucoma prior to obvious neurodegeneration. These dataindicate that C1q in adult glaucomatous retina markssynapses for elimination at early stages of disease, suggest-ing that the complement cascade mediates synapse loss inglaucoma.

Animal Models of Glaucoma 109

Another DBA/2 substrain, DBA/2NNia, also developselevated IOP and demonstrates RGC loss and optic nervedegeneration when aged. However, depletion of cells inthe inner and outer nuclear layers and significant damageof the photoreceptor cells in 15-month-old mice have alsobeen observed.

Transgenic and knock-out approaches have been usedto prospectively develop several mouse models of glau-coma. The main advantage of these approaches is thatanimals within a particular line produce more uniformresponses in terms of IOP elevation and damage to theretina and optic nerve as compared to surgically inducedmodels. A large number of animals may be obtained and notraining is needed to produce affected mice. Several linesof transgenic mice have been developed that contain BACDNAs with a Tyr423His point mutation in the mouseor Tyr437His point mutation in the human MYOCILIN(MYOC) genes. Tyr437His mutation in the MYOC geneleads to severe glaucoma cases in humans, and mouseTyr423His mutation corresponds to this human mutation.However, expression of mutated mouse or human myoci-lin in the eye-drainage structures of mice leads to moder-ate (about 2 mmHg at daytime and 4 mmHg at nighttime)elevation of IOP which is much less dramatic than IOPelevation in humans carrying the same mutation in theMYOC gene. Since these mice demonstrate progressivedegenerative changes in the peripheral RGC layer andoptic nerve with normal organization of the drainagestructures, it has been suggested that these mice representa mouse model of primary open-angle glaucoma. Anothermodel of primary open-angle glaucoma was developedby the expression of a mutated gene for the a1 subunitof collagen type I. This mutation blocks the cleavage ofcollagen by matrix metalloproteinase-1. Transgenic miceexpressing mutated collagen demonstrate elevated IOPwhich increases to a maximum of 4.8 mmHg greater thancontrols at 36 weeks.

A transgenic model of acute angle-closure glaucomawas developed by expression of calcitonin-receptor-likereceptor under the control of a smooth muscle a-actinpromoter. Overexpression of this receptor in the papillarysphincter muscle results in enhanced adrenomedullin-induced sphincter muscle relaxation that leads to abrupttransient rises in IOP in some mice up to a mean level ofabout 50 mmHg between 30 and 70 days of age. Althoughthe aberrant ocular functions of adrenomedullin and cal-citonin-gene-related peptide have not been associatedwith the pathogenesis of human acute glaucoma, it hasbeen suggested that adrenomedullin and its receptor inthe iris sphincter may present novel targets for the treat-ment of angle-closure glaucoma.

Normal-tension mouse models

Mice deficient in the glutamate transporters GLASTor EAAC1 show RGC death and typical glaucomatous

damage of the optic nerve without elevation of IOP. It hasbeen shown that the glutathione levels are decreased inMuller cells of GLAST-deficient mice, while administra-tion of glutamate receptor blocker prevents loss of RGCs.RGCs are more sensitive to oxidative stress in EAAC1-deficient mice. These mice represent a model of normaltension glaucoma and are currently being used to developtherapies directed at IOP-independent mechanisms ofRGC loss.

Developmental mouse models

Defects in genes involved in the development of theanterior eye segment may lead to relatively rare develop-mental glaucomas, which account for less than 1% of allhuman glaucoma cases. Several genes have been impli-cated in congenital glaucoma and anterior segment dys-genesis. They include CYP1B1, FOXC1, FOXC2, PITX2,LMX1b, and PAX6. Although Cyp1b1 knock-out micedo not develop elevated IOP, they have ocular abnormal-ities similar to defects in humans with primary congenitalglaucoma: small or absent Schlemm’s canal, defects inthe trabecular meshwork, and attachment of the iris to thetrabecular meshwork and peripheral cornea. Foxc1–/– micedie at birth, while Foxc1+/– animals are viable but havedefects in the eye-drainage structures in the absence ofIOP changes. Similar eye defects are observed in Foxc2+/–

mice. It has been suggested that Foxc1+/– and Foxc2+/– miceare useful models for studying anterior segment develop-ment and its anomalies, and theymay allow identification ofgenes that interact with Foxc1 and Foxc2 to produce a phe-notype with elevated IOP and glaucoma.

Transgenic mice overexpressing the ocular develop-ment-associated gene (ODAG) in photoreceptors underthe control of mouse Crx promoter exhibit gradual pro-trusion of the eyeballs with dramatically increased IOPthat is not attributable to mechanical block of the aqueoushumor outflow. These transgenic mice demonstrate opticnerve atrophy and impaired retinal development. All ret-inal layers of these transgenic mice are affected, therebydifferentiating this model from a typical glaucomatousretina where morphological changes are detected only inthe RGC layer.

Other Mammalian Models

Several other mammalian models of glaucoma have beendeveloped. Pig eyes are relatively large and, although thedrainage outflow system of the pig eye is slightly differentfrom that of the human eye, the porcine retina is moresimilar to the human retina than that of other large mam-mals (i.e., dog, goat, and cow). Cauterization of three por-cine episcleral veins leads to a 1.3-fold elevation of IOPthat is apparent 3 weeks after the surgery and persists for atleast 21 weeks. It has been shown that endothelium leuko-cyte adhesion molecule 1 (ELAM-1), a molecular marker

110 Animal Models of Glaucoma

for human glaucoma, is also elevated in the trabecularmeshwork of pigs with elevated IOP.

Rabbits are a standard ophthalmic animal model forglaucoma filtration surgery and are often used for thedevelopment of new devices (e.g., drainage implants anddegradable biopolymers) and medical therapies includinggene therapy. At the same time, due to the unique anat-omy of the rabbit eye, laser-induced elevation of IOP, likethat in the monkey eye, is difficult to achieve. Alterna-tively, application of glucocorticoids has been successfullyused to induce ocular hypertension in rabbit model. Inaddition, a line of rabbits with congenital glaucoma hasbeen developed. Thick subcanalicular tissues and thedeposition of extracellular matrix in the trabecular mesh-work appear to contribute to the ocular hypertensionexhibited by this model.

Several purebred dogs develop glaucoma with high fre-quency. Among North American breeds, the highest preva-lence of primary glaucoma is observed in the Americancocker spaniel (5.52%), basset hound (5.44%), and chowchow (4.70%), exceeding that in humans. Lens displace-ment resulting in secondary glaucoma is common in terrierbreeds. The high prevalence of the glaucomas in thesecanine breeds suggests a genetic basis of pathophysiology.

It has been reported that topical application of corti-costeroid induces reproducible elevation of IOP in thecow. The large amount of tissues available from the coweye makes this model useful for biochemical studies.

Nonmammalian Models

Zebrafish

The zebrafish is an excellent model system to studycomplex diseases as it allows one to combine forwardand reverse genetic approaches. The general organizationof the zebrafish eye is similar to the human eye, althoughthe fine details of individual ocular structures are ratherdifferent. In particular, there are significant differences inthe organization of the iridocorneal angle between zebra-fish and mammals. They include the trabecular meshworkand lack of iris muscles as well as ciliary folds in zebrafishas compared to mammals. Even with these limitations inmind, zebrafish have been used as a model organism forglaucoma studies. An accurate method exists to measureIOP in zebrafish which is based on servo-null electro-physiology. Using this method, baseline IOP differenceshave been demonstrated in genetically distinct zebrafishstrains. Among tested strains, the long fin strain (LF) hadthe highest IOP (20.5� 1.2 mm Hg) while the Oregon ABstrain (AB) has the lowest IOP (10.8 � 0.3 mm Hg). At thesame time, these differences in IOP do not lead to detect-able defects of the retina or in visual function. Zebrafishhave also been used to determine the function of severalgenes (foxc1, lmx1b, wdr36, olfactomedin 1, and olfactomedin 2)

implicated in glaucoma. It has been shown that wdr36functions in ribosomal RNA processing and interactswith the p53 stress-response pathway, while olfactomedin1 is essential for optic nerve growth and targeting of theoptic tectum. Thus, zebrafish system may be very usefulto complement studies with other model organisms, butby itself should be used with caution to study glaucoma.

Other Nonmammalian Models

Open-angle glaucoma characterized by elevated IOP canbe induced in domestic chickens or in Japanese quailswhen they are reared under continuous light. Besides,an unknown autosomal dominant mutation in a Slateline of domestic turkeys has been identified that leads tosecondary angle-closure glaucoma. Although these mod-els might be useful to study certain aspects of glaucoma inhumans, one should remember that structural and physi-ological differences between human and bird eyes com-plicate direct comparison.

Drosophila eyes have been suggested as a useful systemfor the discoveryof genes that are associatedwith glaucoma.However, the general organization of human andDrosophilaeyes are very different and data obtained with Drosophilamay not always be relevant to glaucoma in humans.

Conclusion

Animal models have already provided interesting newinformation about potential mechanisms of glaucoma inhumans. However, even in monkey models which mostclosely mimic the human form of the disease, the timecourse of changes in the glaucomatous eyes may be signifi-cantly accelerated as compared with human glaucomatouseyes. Indeed, all of the previously discussed systems are,after all, just models of human glaucoma. Reactions to thesame insult (IOP, expression of the same mutated protein,etc.) may be somewhat different between various animalmodels and humans. Results obtained with these modelsshould not automatically be applied to human conditionand should be confirmed by testing in human subjects whenpossible. Nevertheless, information on molecular mechan-isms of glaucoma obtained using animal models might beextremely valuable to develop new therapeutic approachesfor glaucoma treatment and prevention in humans.

See also: The Development of the Aqueous Humor

Outflow Pathway; Functional Morphology of the Trabe-

cular Meshwork; The Genetics of Primary Open-Angle

Glaucoma: A Review; Molecular Genetics of Congenital

and Juvenile Glaucoma; Myocilin; Primary Open-Angle

Glaucoma; Steroid-Induced Ocular Hypertension and

Effects of Glucocorticoids on the Trabecular Meshwork.

Animal Models of Glaucoma 111

Further Reading

Anderson, M. G., Libby, R. T., Gould, D. B., et al. (2005). High-doseradiation with bone marrow transfer prevents neurodegeneration inan inherited glaucoma. Proceedings of the National Academy ofSciences of the United States of America 102: 4566–4571.

Baulmann, D. C., Ohlmann, A., Flugel-Koch, C., et al. (2002). Pax6heterozygous eyes show defects in chamber angle differentiationthat are associated with a wide spectrum of other anterior eyesegment abnormalities. Mechanisms of Development 118: 3–17.

Harada, T., Harada, C., Nakamura, K., et al. (2007). The potential role ofglutamate transporters in the pathogenesis of normal tensionglaucoma. European Journal of Clinical Investigation 117:1763–1770.

Iwata, T. and Tomarev, S. (2008). Animal models for eye diseases andtherapeutics. In: Conn, P. M. (ed.) Sourcebook of Models forBiomedical Research, pp. 279–287. Totowa, NJ: Humana Press.

Levkovitch-Verbin, H., Quigley, H. A., Martin, K. R., et al. (2002).Translimbal laser photocoagulation to the trabecular meshwork as amodel of glaucoma in rats. Investigative Ophthalmology and VisualScience 43: 402–410.

Libby, R. T., Anderson, M. G., Pang, I., et al. (2005). Inherited glaucomain DBA/2J mice: Pertinent disease features for studying theneurodegeneration. Visual Neuroscience 22: 637–648.

McMahon, C., Semina, E. V., and Link, B. A. (2004). Using zebrafishto study the complex genetics of glaucoma. ComparativeBiochemistry and Physiology – Part C: Toxicology andPharmacology 138: 343–350.

Morrison, J. C., Johnson, E. C., Cepurna, W., and Jia, L. (2005).Understanding mechanisms of pressure-induced optic nervedamage. Retinal Eye Research 24: 217–240.

Pang, I.-H. and Clark, A. F. (2007). Rodent models for glaucomaretinopathy and optic neuropathy. Glaucoma 16: 483–505.

Rasmussen, C. A. and Kaufman, P. L. (2005). Primate glaucomamodels. Journal of Glaucoma 14: 311–314.

Senatorov, V., Malyukova, I., Fariss, R., et al. (2006). Expression ofmutated mouse myocilin induces open-angle glaucoma intransgenic mice. Journal of Neuroscience 26: 11903–11914.

Smith, R. S., John, S. W. M., Nishina, P. M., and Sundberg, J. P. (eds.)(2002). Systematic Evaluation of the Mouse Eye. Boca Raton, FL:CRC Press.

Weinreb, R. N. and Lindsey, J. D. (2005). The importance of models inglaucoma research Volume. Journal of Glaucoma 14: 302–304.