The development of age-related macular degeneration (AMD) experimental models
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首席医学网
2007年08月31日 21:51:18 Friday
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作者：Wei Jiang, George C.Y. Chiou 作者单位：Institute of Ocular Pharmacology and Department of Neuroscience and Experimental Therapeutics, Texas A&M University System Health Science Center College of Medicine, College Station, TX 77843, USA
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Abstract This article reviews different experimental models of age-related macular degeneration (AMD) used in recent studies. The most widely used one is Laser-induced choroidal neovascularization (CNV), which represents the late severe stage in the exudative form of AMD. Other models are based on several different pathogenesis, like geographic atrophy, drusen formation or multifactorial effects, like age, light, high fat, etc. It is hoped that this review could become a good reference for researchers who need to choose suitable models for AMD study.
· KEYWORDS: age-related macular degeneration; model
INTRODUCTION
Age-related macular degeneration (AMD) is the leading cause of poor vision among people aged over 65. It has many clinicopathologic signs, numerous pathogenesis and various etiologies. The treatment for this disease is limited. Many researches studying this disease have established some experimental models both in vivo and in vitro. The basic foundation of these models was based on etiology or acology, which could also be classified into two types : wet- and dry-AMD. There is no perfect model representing exactly the same conditions to what really happened in the patient's eyes. More over, what happened in one kind of model usually can not be used to explain a single theory either. In this review, we try to introduce these experimental AMD models on the bases of pathology, pathogenesis, etiology, and others.
PATHOLOGY OF AMD
Neovascularization Choroidal neovascularization (CNV) is the leading cause of wet-AMD, which affects mostly the visual acuity. There are different methods available to induce CNV in experiments. The most commonly used one is the laser beam. The purpose of this model is to perforate the Bruch's membrane to trigger CNV formation. Using a slit lamp delivery system, 2-8 spots are placed through lens at equal distances around the optic discs with acute vapour bubbles. Those spots having no bubble or having subretinal hemorrhage are excluded. Animals used can be rats, mice or pigs. The laser used can be krypton red laser [1], green argon laser [2,3] and diode laser [4-6]. These methods can develop stable CNV quickly.
Vascular endothelial growth factor (VEGF) is closely related to the formation of CNV [7].Thus, some methods were based on the increasing levels of VEGF in the eyes. One is using adeno-associated viral vector encoding human VEGF165 injected into the subretinal space (SRS) of Sprague-Dawley or Long Evans rats, in which the CNV persisted for more than 20 months [8]. Schwesinger et al [9]established a transgenic murine model through the overexpression of VEGF by the retinal pigment epithelium to induce CNV. They introduced a tissue-specific murine retinal pigment epithelium promoter coupled with murine VEGF164 cDNA with a rabbit b-globin-3 UTR into the genome of albino mice. The expression of VEGF protein was increased in both retinal pigment epithelium and choroids, with the increase of intravascular adherent leukocytes and vessel leakage.
Another transgenic mouse model is prokineticin 1 (hPK1), a mitogen of fenestrated endothelium. They generated transgenic mice with an expression of hPK1 in the retina using rhodopsin promoter. Consequently, enlarged vascular bed of choroid, resembling CNV, was observed without any morphological changes in the retinal vasculature. The major fluorophore of lipofuscin was highly accumulated in the transgenic mouse eyes as compared to controls[10].
Neovascularization can be easily formed by ischemia. A hyperoxia-induced retinal ischemia and neovascularization occurred in all mice's eyes by means of putting one-week-old mice into 750mL/L O2 for 5 days, from postnatal day 17 (P17) to postnatal day 21 (P21) ,and then into room air [11]. The time exposed to oxygen could be changed from P7 to P12[12] or from within 2 hours of birth to P14[13].The concentration of the oxygen could be changed into 730mL/L[14] or 24 hours alternating cycles between 500mL/L O2 and 100mL/L O2[13].This type of neovascula- rization develops in the retina, but not in choroids.
An isolated neovascular structure model could be obtained by corneas consisting of an easily accessible monolayer-like neovascular net within a transparent matrix[15]. Using this model, researches could evaluate the efficacy of drugs or photodynamic therapy on ocular neovascularization [16, 17]. Another kind of isolated neovascular structure is the highly vascularized 8 to 9-day-old chicken chorioallantoic membrane, which is similar to the rapid growth of blood vessels in the wet form of AMD[18].
Based on abovementioned models, some important AMD related data could be generated, with mouse serum albumin (MSA), carboxyethylpyrrole (CEP)-MSA, or VEGF[19].
In vitro experiment, using choroidal endothelial cells (CECs) which involved in the process of CNV formation is a good model for evaluating the anti- proliferation effect by drugs [20].
Drusen Drusen is a typical clinicopathologic entity in nonexudative macular degeneration, which is caused by the change of retinal pigment epithelium and Bruch's membrane. There is a spontaneous model of Rhesus macaques (Macaca mulatta) for age related macular drusen. The prevalence and severity of drusen formation in their eyes are linearly related to increasing age and are significantly higher in specific maternal lineages (matrilines) [21]. Several researches used this model for studying the mechanism and treatment of AMD[22, 23].
Basal Laminar Deposit Similar to drusen, basal laminar deposit (BLD) is another typical signal of dry-AMD development and led by extracellular deposits. BLD is located between the cell membrane of the retinal pigment epithelium (RPE) and its basement membrane , while drusen is located in between the basement membrane of the RPE and the remainder of Bruch's membrane, or external to Bruch's membrane[24,25]. An experiment showed that transgenic mice expressing the human apolipoprotein-E (apo-E) 3-Leiden gene (and producing a dysfunctional form of human apo-E3) on a high fat/cholesterol (HFC) diet or on a normal mouse fed for 9 months. All eyes of the apo-E3- Leiden mice on an HFC diet contained BLD ( class 1 to class 3), whereas two of six apo-E3- Leiden mice on normal chow showed only BLD class 1. So these apo-E3- Leiden mice can be used as animal model for studying the pathogenesis of BLD which could be enhanced by HFC diet[26].
RPE Cells Retinal pigment epithelial (RPE) cells are very important in eye's physiological function. Some considered that AMD is caused by loss or disfunction of RPE cells which leads to abnormal build-up of photoreceptor outer segment breakdown products. A transgenic mouse line (mcd/mcd) expressed a mutated form of cathepsin D which is enzymatically inactive thus impairing processing of phagocytosed photoreceptor outer segments in the RPE cells. Histological studies showed proliferation of RPE cell, degeneration of photoreceptor, shortening of photoreceptor outer segments, and accumulation of immunoreactive photoreceptor breakdown products in the RPE cells [27].
Pigmented dystrophic Royal College of Surgeons (RCS) rats have been widely used by various researches, because most photoreceptors of these rats die during the first three months of life. Due to a genetic defect in photoreceptor outer segment, and phagocytosis by the adjacent RPE, the RCS rats could be used for the treatment research on RPE protection and on AMD improvement[28]. Another experiment for RPE degeneration uses a single injection of sterile 1% solution of NaIO3 in saline into the tail vein. The final dose used was 50mg/kg body weight, which could produce a progressive degeneration of the RPE and the neural retina[29]. If the retinal pigment epithelium is debrided in the porcine eye, atrophy of the choriocapillaris appeared within 1 week. The method uses pars plana vitrectomy firstly, then creating neurosensory retinal detachments by injecting mitomycin C and edetic acid into the subretinal space. Twenty minutes later, the retinal pigment epithelium is debrided, and the retina is reattached with a fluid-gas exchange. So this model could be used for nonexudative age-related macular degeneration[30].
In in-vitro experiments, RPE cells were widely used[31],which could be seen as the outer blood-retinal barrier when they grow on coated flasks [32] and in which sub-RPE deposits could be assessed by machines such as electron microscopy [33].
PATHOGENESIS OF AMD
Oxidative Damage Oxidative stress, having long been linked to the age-related and degenerative diseases, is implicated in the pathogenesis of AMD. Mice deficient in Cu, Zn-superoxide dismutase (SOD) of different ages showed that the older animals had drusen, thickened Bruch's membrane, and choroidal neovascularization. The number of drusen increased with age, and if exposuring of young SOD1 knock out mice to excess light, drusen could be induced and RPE cells could be oxidatively damaged [34]. Because the oxidative damage is likely to be the photoreactive pigments which accumulate progressively and constitute the lipofuscin of RPE cells. RPE cells are always used in in-vitro experiments [35].
Using hydroquinone (HQ) in cultured RPE could upregulate nonlethal blebbing and decrease extracellular matrix (ECM) turnover. Animals exposed to oral HQ induced nonlethal bleb injury and sub-RPE deposits. These results were considered as nonlethal oxidant injury induced by HQ [36].
Complement Component Some works demonstrated that complement components C3 and C5 are constituents of drusen in patients with AMD. Mice deficient in monocyte chemoattractant protein-1(Ccl-2; also known as MCP-1) or its cognate C-C chemokine receptor-2 (Ccr-2) developed cardinal features of AMD, including accumulation of lipofuscin in drusen and in beneath the RPE plus photoreceptor atrophy and CNV [37].
Lipid Accumulation Lipids could be involved in many aging diseases. An experiment using LDL receptor deficient mice (a atherosclerotic murine model) being fed with standard or a high fat (HF) diets was used to study the changes on mice's eyes. They found lipid particles accumulated in Bruch's membrane (BrM) which was further increased after fat intake. VEGF expression was found in the outer retinal layers and appeared to correlate with the amount of lipid particles present in BrM [38].
Iron Ferroxidase ceruloplasmin (Cp) and/or hephaestin (Heph) deficient mice had been used to study the effect of iron on the development of AMD. These mice had age-dependent RPE hypertrophy, hyperplasia and death coupled with photoreceptor degeneration and subretinal neovascularization, providing a model for some features of the human retinal diseases aceruloplasminemia and age-related macular degeneration [39].
ETIOLOGY OF AMD
Age and High-fat Diet Advanced age is considered as the first etiology in AMD, which have been confirmed by many clinic statistics and researches. Besides, epidemiologic data also indicated that dietary fats, especially polyunsaturated fats, were associated with AMD [40]. There were also some related researches which showed that only old age (male 65-123 weeks, female 75-127 weeks) or high-fat chow (Diet 5015; PMI Nutrition International Test Diet) could elicit pathogenesis of AMD in mouse's eyes [41, 42].
Light Light exposure, inducing oxidative damage, is suspected to play an important role in the etiology of AMD. Different kind of lights were used on animal eyes, such as blue light (14μW/cm2; bandwidth, 390 to 430nm)[43], nonphototoxic levels of argon laser 488 nm blue-green light[42] and 15 000 lux of diffuse white fluorescent light (TLD-36 W/965 tubes, Philips; ultraviolet-impermeablediffuser).The last one was used for 2h on dilated pupils of already dark- adapted animals by being maintained in dim red light, those animals were kept in darkness at all time until analysis [44].
Smoke and Alcohol Cigarette smoke has been indicated by epidemiologic studies that it is the single greatest environmental risk factor for both dry and wet AMD[45].One experiment[46]was conducted by exposing mice to inhaled cigarette smoke by using of a custom-built microprocessor- controlled cigarette-smoking machine or by feeding mice with a defined cigarette smoke component , HQ, as mentioned above[36]. The results of this experiment showed the formation of sub-RPE deposits, thickening of Bruch's membrane, and accumulation of deposits within Bruch’s membrane. On another experiment, mice were fed with nicotine in their drinking water (100μg/mL) for 4 weeks, the nicotine increased size and severity of experimental CNV in this mouse model [47]. In order to investigate whether alcohol influences the development of CNV, Bora et al [48] gave 8g/kg alcohol and regular diet to rats for 10 weeks. The result showed that fatty acid ethyl ester synthase (FAEES) activity was increased 4.0-fold in the choroid of alcohol-treated rats as compared with controls. The amount of ethyl esters produced in the choroid of 10 week alcohol-fed rats was 7.4-fold more than rats fed alcohol for 1 week. And the size of CNV induced by laser treatment increased by 28% in alcohol-fed rats.
Gene Beside environmental factors, gene also plays an important role in the development of AMD. Thus, some models used are transgenic animals based on different etiology. Eyes of apolipoprotein B100 (APO B100) transgenic mice treated with blue-green light showed a high frequency of "moderate BLD", whereas the nonexposed eyes did not [42]. Among eyes of aged, targeted replacement mice expressing human apoE2, apoE3 and apoE4, apoE4 mice were the most severely affected, which developed a constellation of changes that mimic the pathology associated with human AMD[41]. Fas (CD95)-deficient (lpr) and FasL-defective (gld) mice had a significantly increased incidence of neovascularization. In gld mice there was massive subretinal neovascularization with uncontrolled growth of vessels.
Cultured choroidal endothelial cells were induced to undergo apoptosis by retinal pigment epithelial cells through a Fas-FasL interaction [49].
OTHERS
Physical Method Matrigel, a basement membrane extract which is solidifiable after implantation in tissue could induce neovascularization and focal retinal degeneration after subretinal injected in mice[50].
Other Diseases Since the clinical manifestation and pathology of some other diseases are similar to AMD's, researchers could use these models to investigate AMD. For example, Stargardt macular dystrophy (STGD), which is characterized as AMD by the accumulation of high levels of lipofuscin in the retinal pigment epithelium. It precedes to degeneration of the photoreceptors in the macula and atrophy of RPE, just like the transgenic ELOVL4 Mice [51,52]. Different from STGD which likes dry-AMD, Sorsby's fundus dystrophy (SFD) is a rare autosomal dominant disorder that results in degeneration of the macular region of the retina and leads to the rapid loss of central vision likes wet or exudative form of AMD [53].
CONCLUSION
Age-related macular degeneration (AMD), the most common cause of blindness in the elderly in developed countries, has a complex aetiology with both genetic and environmental factors playing roles. It also has a complex pathology and a series of clinical features. Till now, there has no proper model which could reflect all of the related factors. The established models could only partly represent the development of AMD. Laser-induced CNV is the most commonly used .This method perforates the Bruch's membrane so that CNV could easily and quickly developed. However, not only Bruch's membrane, retina and part of choroid could also be damaged around the laser spot, which obviously doesn't mimic completely the pathology of clinical AMD. Furthermore, although there are many experiments using mice and rat, these animals have no macula at all. So when we want to investigate action mechanisms or treatments of AMD, we should choose the most closely related model but not just one kind of model. Besides, how to evaluate the development of pathological changes and to study the effect of different treatments are another important topics. The best we can do today is to pick the best model which mimic human AMD and show the quantitative changes, even though, we might loose some important data or might be still far away from clinical reality. Therefore, new animal models are still needed to be created.
【参考文献】
1 Ciulla TA, Criswell MH, Danis RP, Fronheiser M, Yuan P, Cox TA, Csaky KG, Robinson MR. Choroidal neovascular membrane inhibition in a laser treated rat model with intraocular sustained release triamcinolone acetonide microimplants. Br J Ophthalmol ,2003;87:1032-1037
2 Rakic JM, Lambert V, Munaut C, Bajou K, Peyrollier K, Alvarez-Gonzalez ML, Carmeliet P, Foidart JM, No?觕l A. Mice without uPA, tPA, or Plasminogen Genes Are Resistant to Experimental Choroidal Neovascularization. Invest Ophthalmol Vis Sci ,2003;44(4):1732-1739
3 Semkova I, Kreppel F, Welsandt G, Luther T, Kozlowski J, Janicki H, Kochanek S, Schraermeyer U. Autologous transplantation of genetically modified iris pigment epithelial cells: A promising concept for the treatment of age-related macular degeneration and other disorders of the eye. Proc Natl Acad Sci , 2002;99(20):13090-13095
4 Bora PS, Hu Z, Tezel TH, Sohn JH, Kang SG, Cruz JMC, Bora NS, Garen A, Kaplan HJ. Immunotherapy for choroidal neovascularization in a laser-induced mouse model simulating exudative (wet) macular degeneration. Proc Natl Acad Sci ,2003;100(5):2679-2684
5 Takahashi H, Obata R, Tamaki Y. A Novel Vascular Endothelial Growth Factor Receptor 2 Inhibitor, SU11248, Suppresses Choroidal Neovascularization In Vivo. J Ocular Pharmacol Ther ,2006;22(4):213-218
6 Balaggan KS, Binley K, Esapa M, MacLaren RE, Iqball S, Duran Y, Pearson RA, Kan O, Barker SE, Smith AJ, Bainbridge JWB, Naylor S, Ali RR. EIAV vector- mediated delivery of endostatin or angiostatin inhibits angiogenesis and vascular hyperpermeability in experimental CNV. Gene Ther ,2006;13:1153-1165
7 Campochiaro PA. Retinal and choroidal neovascularization. J Cell Physiol ,2000;184:301-310
8 Wang F, Rendahl KG, Manning WC, Quiroz D, Coyne M, Miller SS. AAV-Mediated Expression of Vascular Endothelial Growth Factor Induces Choroidal Neovascularization in Rat. Invest Ophthalmol Vis Sci ,2003;44(2):781-790
9 Schwesinger C, Yee C, Rohan RM, Joussen AM, Fernandez A, Meyer TN, Poulaki V, Ma JJK, Redmond TM, Liu S, Adamis AP, D'Amato RJ. Intrachoroidal Neovascularization in Transgenic Mice :Overexpressing Vascular Endothelial Growth Factor in the Retinal Pigment Epithelium. Am J Patholmol ,2001;158(3):1161-1172
10 Tanaka N, Ikawa M, Mata NL Verma IM. Choroidal eovascularization in Transgenic Mice Expressing Prokineticin 1: An Animal Model for Age-Related Macular Degeneration. Mol Ther ,2006;13(3):609-616
11 Smith LE, Wesolowski E, McLellan A, Kostyk SK, D'Amato R, Sullivan R, D'Amore PA. Oxygen-induced retinopathy in the mouse. Invest Ophthalmol Vis Sci ,1994;35:101-111
12 Semkova I, Kreppel F, Welsandt G, Luther T, Kozlowski J, Janicki H, Kochanek S, Schraermeyer U. Autologous transplantation of genetically modified iris pigment epithelial cells: A promising concept for the treatment of age-related macular degeneration and other disorders of the eye. Proc Natl Acad Sci , 2002;99(20):13090-13095
13 Kinose F, Roscilli G, Lamartina S, Anderson KD, Bonelli F, Spence SG, Ciliberto G, Vogt TF, Holder DJ, Toniatti C, Thut CJ. Inhibition of retinal and choroidal neovascularization by a novel KDR kinase inhibitor. Mol Vis ,2005;11:366-373
14 Raisler BJ, Berns KI, Grant MB, Beliaev D, Hauswirth WW. Adeno-associated virus type-2 expression of pigmented epithelium-derived factor or Kringles 1-3 of angiostatin reduce retinal neovascularization. Proc Natl Acad Sci ,2002;99(13):8909-8914
15 IonitaM A, IonR M, Carstocea B. Photochemical and photodynamic properties of vitamin B2--riboflavin and liposomes. Oftalmologia ,2003;58(3):29-34
16 Ionita MA, Ion RM, Carstocea B, Gafencu OL, Niculescu VI. Photodynamic occlusion of ocular neo-vascularization with B2 vitamin. Oftalmologia ,2002;54(3):82-86
17 Eyetech Study Group. Preclinical and phase 1A clinical evaluation of an anti-VEGF pegylated aptamer (Eye001) for the treatment of exudative age-related macular degeneration. Retina ,2002;22(2):143-152
18 Samkoe KS, Cramb DT. Application of an ex ovo chicken chorioallantoic membrane model for two-photon excitation photodynamic therapy of age-related macular degeneration. J Biomed Opt , 2003;8(3):410-417
19 Ebrahem Q, Renganathan K, Sears J, Vasanji A, Gu X, Lu L, Salomon RG, Crabb JW, Anand-Apte B. Carboxyethylpyrrole oxidative protein modifications stimulate neovascularization: Implications for age-related macular degeneration. Proc Natl Acad Sci ,2006;103(36):13480-13484
20 Hoffmann S, Balthasar S, Friedrichs U, Ehren M, Ryan SJ, Wiedemann P. Inhibitory effects of verapamil isomers on the proliferation of choroidal end othelial cells. Graefes Arch Clin Exp ophthalmol ,2006;244(3):376-381
21 Hope GM, Dawson WW, Engel HM, Ulshafer RJ, Kessler MJ, Sherwood MB. A primate model for age related macular drusen. Br J Ophthalmol ,1992;76(1):11-16
22 Neuringer M, Sandstrom MM, Johnson EJ, Snodderly DM. Nutritional Manipulation of Primate Retinas, I: Effects of Lutein or Zeaxanthin Supplements on Serum and Macular Pigment in Xanthophyll-Free Rhesus Monkeys. Invest Ophthalmol Vis Sci ,2004;45(9):3234-3243
23 Nicolas MG, Fujiki K, Murayama K, Suzuki MT, Shindon, Hotta Y, Iwata F, Fujimura T, Yoshikawa Y, Cho F, Kanai A. Studies on the Mechanism of Early Onset Macular Degeneration in Cynomolgus Monkeys. II. Suppression of Metallothionein Synthesis in the Retina in Oxidative Stress. Exp Eye Res ,1996;62:399-408
24 Green WR, Enger C. Age-related macular degeneration histopathologic studies. The 1992 Lorenz E. Zimmerman Lecture. Ophthalmology ,1993;100:1519-1535
25 Kliffen M, vd Schaft TL, Mooy CM, d Jong PTVM. Morphologic changes in age-related maculopathy. Microsc Res Tech ,1997;36:106-122
26 Kliffen M, Lutgens E, Daemen MJ, de Muinck ED, Mooy CM, de Jong PT. The APO*E3-Leiden mouse as an animal model for basal laminar deposit. Br J Ophthalmol ,2000;84:1415-1419
27 Rakoczy PE, Zhang D, Robertson T, Barnett NL, Papadimitriou J, Constable IJ, Lai CM. Progressive Age-Related Changes Similar to Age-Related Macular Degeneration in a Transgenic Mouse Model. Am J Pathol ,2002;161(4):1515-1524
28 Coffey PJ, Girman S, Wang SM, Hetherington L, Keegan DJ, Adamson P, Greenwood J, Lund RD. Long-term preservation of cortically dependent visual function in RCS rats by transplantation. Nature Neurosci ,2002;5(1):53-56
29 Atmaca-Sonmez P, Li Y, Yamauchi Y, Schanie CL, Ildstad ST, Kaplan HJ, Enzmann V. Systemically transferred hematopoietic stem cells home to the subretinal space and express RPE-65 in a mouse model of retinal pigment epithelium damage. Exp Eye Res ,2006;83(5):1295-1302
30 Del Priore LV, Kaplan HJ, Hornbeck R, Jones Z, Swinn M. Retinal pigment epithelial debridement as a model for the pathogenesis and treatment of macular degeneration. Am J Ophthalmol ,1996;122(5):629-643
31 Ferrington DA, Tran TN, Lew KL, Remmen HV, Gregerson DS. Different death stimuli evoke apoptosis via multiple pathways in retinal pigment epithelial cells. Exp Eye Res ,2006;83(3):638-650
32 Penfold PL, Wen L, Madigan MC, Gillies MC, King NJC, Provis JM. Triamcinolone acetonide modulates permeability and intercellular adhesion molecule-1 (ICAM-1) expression of the ECV304 cell line: implications for macular degeneration. Clin Exp Immunol ,2000;121(3):458-465
33 Amin S, Chong NHV, Bailey TA, Zhang J, Knupp C, Cheetham ME, Greenwood J, Luthert PJ.Modulation of Sub-RPE Deposits In Vitro: A Potential Model for Age-Related Macular Degeneration. Invest Ophthalmol Vis Sci ,2004;45(5):1281-1288
34 Imamura Y, Noda S, Hashizume K, Shinoda K, Yamaguchi M, Uchiyama S, Shimizu T, Mizushima Y, Shirasawa T, Tsubota K. Drusen, choroidal neovascularization, and retinal pigment epithelium dysfunction in SOD1-deficient Mice: A model of age-related macular degeneration. Proc Natl Acad Sci ,2006;103(30):11282-11287
35 Zhou JL, Gao XQ, Cai B, Sparrow JR. Indirect Antioxidant Protection Against Photooxidative Processes Initiated in Retinal Pigment Epithelial Cells by a Lipofuscin Pigment. Rejuvenation Res ,2006; 9(2):256-263
36 Marin-Casta?觡o ME, Striker GE, Alcazar O, Catanuto P, Espinosa-Heidmann DG, Cousins SW. Repetitive Nonlethal Oxidant Injury to Retinal Pigment Epithelium Decreased Extracellular Matrix Turnover In Vitro and Induced Sub-RPE Deposits In Vivo. Invest Ophthalmol Vis Sci ,2006;47(9): 4098-4112
37 Ambati J, Anand A, Fernandez S, Sakurai E, Lynn BC, Kuziel WA, Rollins BJ, Ambati BK. An animal model of age-related macular degeneration in senescent Ccl-2- or Ccr-2- deficient mice. Nat Med ,2003;11(9):1390-1397
38 Rudolf M, Winkler B, Aherrahou Z, Doehring LC, Kaczmarek P, Schmidt-Erfurth U. Increased expression of vascular endothelial growth factor associated with accumulation of lipids in Bruch's membrane of LDL receptor knockout mice. Br J Ophthalmol ,2005;89:1627-1630
39 Hahn P, Qian Y, Dentchev T, Chen L, Beard J, Harris ZL, Dunaief JL. Disruption of ceruloplasmin and hephaestin in mice causes retinal iron overload and retinal degeneration with features of age-related macular degeneration. Proc Natl Acad Sci ,2004;101(38):13850-13855
40 Seddon JM, Rosner B, Sperduto RD, Yannuzzi L, Haller JA, Blair NP, Willett W. Dietary fat and risk for advanced age-related macular degeneration. Arch Ophthalmol ,2001;119:1191-1199
41 Malek G, Johnson LV, Mace BE, Saloupis P, Schmechel DE, Rickman DW, Toth CA, Sullivan PM, Bowes Rickman C. Apolipoprotein E allele-dependent pathogenesis:A model for age-related retinal degeneration. Proc Natl Acad Sci ,2005;102(33):11900-11905
42 Espinosa-Heidmann DG, Sall J, Hernandez EP, Cousins SW.Basal Laminar Deposit Formation in APO B100 Transgenic Mice: Complex Interactions between Dietary Fat, Blue Light, and Vitamin E. Invest Ophthalmol Vis Sci ,2004;45(1):260-266
43 Gottsch JD, Bynoe LA, Harlan JB, Rencs EV, Green WR. Light-induced deposits in Bruch's membrane of protoporphyric mice. Arch Ophthalmol ,1993;111(1):126-129
44 Grimm C, Wenzel A, Hafezi F, Yu S, Redmond TM, Remé CE. Protection of Rpe65-deficient mice identifies rhodopsin as a mediator of light-induced retinal degeneration. Nature Genetics ,2000;25:63-66
45 Evans JR. Risk factors for age-related macular degeneration. Prog Retin Eye Res ,2001;20:227-253
46 Espinosa-Heidmann DG, Suner IJ, Catanuto P, Hernandez EP, Marin-Castano ME, Cousins SW. Cigarette Smoke-Related Oxidants and the Development of Sub-RPE Deposits in an Experimental Animal Model of Dry AMD. Invest Ophthalmol Vis Sci ,2006;47(2):729-737
47 Su?觡er IJ, Espinosa-Heidmann DG, Marin-Castano ME, Hernandez EP, Pereira-Simon S, Cousins SW.Nicotine Increases Size and Severity of Experimental Choroidal Neovascularization. Invest Ophthalmol Vis Sci ,2004;45(1):311-317
48 Bora PS, Kaliappan S, Xu Q , Kumar S, Wang Y, Kaplan HJ, Bora NS. Alcohol linked to enhanced angiogenesis in rat model of choroidal neovascularization. Fed Eur Biochem Soci J ,2006;273:1403-1414
49 Kaplan HJ, Leibole MA, Tezel T, Ferguson TA. Fas ligand (CD95 ligand) controls angiogenesis beneath the retina. Nat Med ,1999;5(3):292-297
50 Shen D, Wen R, Tuo J, Bojanowski CM, Chan CC. Exacerbation of Retinal Degeneration and Choroidal Neovascularization Induced by Subretinal Injection of Matrigel in CCL2/MCP-1-Defi cient Mice. Ophthalmic Res ,2006;38:71-73
51 Karan G, Lillo C, Yang Z, Cameron DJ, Locke KG, Zhao Y, Thirumalaichary S, Li C, Birch DG, Vollmer-Snarr HR, Williams DS, Zhang K. Lipofuscin accumulation, abnormal electrophysiology,and photoreceptor degeneration in mutant ELOVL4 transgenic mice: A model for macular degeneration. Proc Natl Acad Sci ,2005;102(11):4164-4169
52 Raz-Prag D, Ayyagari R, Fariss RN, Mandal MNA, Vasireddy V, Majchrzak S, Webber AL, Bush RA, Salem N Jr, Petrukhin K, Sieving PA. Haploinsufficiency is not the key mechanism of pathogenesis in a heterozygous Elovl4 knockout mouse model of STGD3 disease. Invest Ophthalmol Vis Sci ,2006;47(8): 3603-3611
53 Li Z, Clarke MP, Barker MD, McKie N. TIMP3 mutation in Sorsby's fundus dystrophy: molecular insights. Expert Rev Mol Med ,2005;31;7(24):1-15
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