Index

A ARMS2 , 369–370 A AV. See Adeno-associated virus (AAV) chronic age-related disease , 727 ABCA4 , 408–409 diagnostic tools , 274 ABCA4 −/− , mouse eyecups , 763–764 histopathological analysis , 726 Abe, T. , 305 HTRA1 , 370 ABI/SOLiD platform , 755 neovascular ocular diseases , 246 Ablonczy, Z. , 75 retina , 272 (ACHM) , 183. See also Cyclic retina autophagy ( see Autophagy) nucleotide-gated (CNG) channels retinal neovascular disorders , 255 Adamowicz, M. , 573 risk factors , 726 Adaptive optics (AO) imaging therapeutic approaches , 270 analysis and interpretation , 451–452 VEGF levels , 272 bulls’s eye maculopathy , 454–455 Aguayo , 161 clinical examination , 452 Aguirre, G.D. , 321, 353, 611 dominant drusen , 452–454 Ahern, K. , 553 retinal atrophy and visual loss , 454–456 AIF. See Apoptosis-inducing factor (AIF) Adeno-associated virus (AAV) , 180 Airaksinen, S. , 668 rescued retinal function , 202–203 Akopian, A. , 739 retinal structure integrity , 201–202 Albarracin, R.S. , 121 RHO301 gene expression , 201 Ali, R.R. , 17, 177 usher syndrome type 1B , 239 Allikmets, R. , 368 XIAP protein , 211–212 All- trans -retinal dimer phosphatidyletha- Adenosine 5¢ -triphosphate (ATP) , 813 nolamine , 763–764 degradation , 814 Al-Ubaidi, M.R. , 835 and purinergic receptors , 813 Ambati, J. , 3 storage and release of , 814 AMD. See Age-related macular degeneration A2-dihydropyridine-phosphatidylethanolamine (AMD) (A2-DHP-PE) , 764–765 AMP-activated protein kinase (AMPK) ADRP. See Autosomal dominant retinitis cellular process, role in , 746 pigmentosa (ADRP) and RPE cell function Advanced glycation end product (AGE) , 765 allosterical activation , 746 A2E , 725, 763 cell barrier function , 747–748 AFF. See Autofl uorescent foci (AFF) cell infl ammatory response , 748–749 Age-related macular degeneration (AMD) , 62, cell survival , 749 64, 65, 67–68 phagocytosis , 748 angiogenic response , 273 via Thr172 Pphosphorylation , 746–747

M.M. LaVail et al. (eds.), Retinal Degenerative Diseases, Advances in Experimental 843 and Biology 723, DOI 10.1007/978-1-4614-0631-0, © Springer Science+Business Media, LLC 2012 844 Index

AMP-activated protein kinase infl ammation and immune system , 12 (AMPK) (cont.) proinfl ammatory factors , 14 Ser/Thr kinase , 746 protein modifi cation , 11 subunit , 746 role of autoimmunity , 13–14 Amyloid- b role Autophagy , 208 AMD , 67–68 AMD , 87–88 cytotoxic, neural retina , 69–70 molecular events , 84–85 drusen component , 68 neural retina , 85–86 proinfl ammatory retina , 70–71 RPE , 86–87 RPE cell structure and function , 68–69 signaling mechanisms , 85 Amyloid precursor protein (APP) , 68 Autophagy-related proteins (Atg) , 84 Anand-Apte, B. , 261, 293 Autosomal dominant cone and cone-rod Anderson, R.E. , 129 dystrophy Angiogenesis , 681 characterisation , 337 Animal model genetic analyses , 338 rd 10 mice, RPE sheet analysis (see Rd10 hereditary retinal dystrophies , 337 mice, retinal degeneration model) mutation spectrum , 338–340 ROM-1 overexpression patients and clinical examinations , 338 electron microscopy , 635 Autosomal dominant retinitis pigmentosa , 634–635 (ADRP) , 191, 215, 500–502, 573 gel electrophoresis , 634 AAV gene delivery transgenic mice , 634 rescued retinal function , 202–203 western blot analysis , 634 retinal structure integrity , 201–202 Annear, M.J. , 177 RHO301 gene expression , 201 Annexin 2 (anxA2) , 720 animal models , 200 Apolipoprotein , 726 electroretinography , 200–201 Apoptosis , 207 outer nuclear layer , 201 Apoptosis-inducing factor (AIF) , 210 RHO301 gene cloning , 200 Apoptotic cell death , 554 Axonal guidance. See Homeobox Aranesp/AMG114 , 138, 139 Ayyagari, R. , 225 Arinobu, D. , 823 Aron, L. , 415 Arrestin 1 (Arr1) B dark-or light-adapted retinas , 793–795 Bachor, T.P. , 101 protein–protein interaction , 793 Bagheri, N. , 479 Arylalkylamine N-acetyltransferase Bai, L. , 183 (AANAT) , 824 Bainbridge, J.W. , 177 Aryl hydrocarbon receptor (AhR) Bai, Y. , 299 AMD pathogenesis , 55–56 Balaggan, K.S. , 271 cellular oxidative stress response , 54 Balb-c male mice , 102 cigarette smoke , 52 Bandyopadhyay, M. , 23 genetic linkage and genome-wide Bardet–Biedl syndrome (BBS) , 533 association study , 51–52 Barker, S.E. , 177, 180 molecular and biological mechanism , 51 Barrier modulation proteosomal degradation , 54–55 characteristics , 157–158 RPE cellular response, oxidant injury , Claudin-5 , 156 52–53 IMPDH1gene , 156, 157 Association for Research in Vision and potential benefi ts , 156, 157 , 642 RPE , 157 Autofl uorescent foci (AFF) , 464 Barstable, 758 Autoimmune biomarkers Bartoe, J.T. , 177 “after-the-fact” phenomenon , 14 Basavarajappa, D.K. , 829 AMD pathogenesis , 12–13 Basic helix-loop-helix (bHLH) , 686 immunomics , 15 Bassoon KO mice , 740, 741 Index 845

b -carotene monooxygenase 1 (BCMO1) , 168 IMPDH1gene , 156, 157 BCM. See Blue cone (BCM) potential benefi ts , 158 Beaulieu, C. , 371 RPE , 157 Becerra, S.P. , 799 tight junctions , 155–156 Bech-Hansen, N.T. , 371 Blue cone monochromacy (BCM) , 599 Becirovic, E. , 183 Blue light damage Beck, S.C. , 183 apoptosis , 619 Bell, B.A. , 459, 479 cryosection , 623 Beltran, W.A. , 353 DNA microarray , 620 Bennett, J. , 129 histological investigation , 629 Bernd, A. , 471 MacGreen mice , 620 Best corrected visual acuity (BCVA) , 472 microglia accumulation , 622–623 Best disease , 604 quantitative real-time PCR , 620–621 BEST1 missense mutations retinal cross sections and whole mounts, 620 anion channel malfunction , 612 retinal degeneration , 619 BVMD , 611, 616 RNA isolation and reverse transcription, 620 canine bestrophin-1 topology , 613–614 transcriptomic changes cellular homeostasis , 616 DNA microarray analysis , 623, 624 comparative protein modeling , 613–615 expression , 625–628 membrane protein , 616 microarrays algorithm , 624 protein structure , 613 qPCR validation , 629 topological model , 612–613 Blue native-PAGE Bestrophin-1. See also BEST1 missense analysis of , 773 mutations detergents , 770 anion conductance loss , 604 protein complex seperation , 774 cytoplasmic function , 607–609 Boatright, J.H. , 641 function , 604 Bonilha, V.L. , 479 localization , 604–606 Bothnia-type retinal dystrophy retinal degeneration , 603 11- cis -retinal vitelliforme macular dystrophy , 604 illumination , 590 Best vitelliform macular dystrophy (BVMD) , photoisomerization , 592–593 604, 611, 616 CRALBP WT and R234W Betacellulin (BTC) expression, purifi cation, angiogenesis , 295 crystallization , 590 biological functions , 294 ligand-binding cavity , 592 future aspects , 296 structure determination , 590–592 role, retina , 295 crystallographic statistics , 593 structure and expression , 294 RLBP1 gene , 589 Bian, Q. , 43 Boulton, M.E. , 83, 726 Biel, M. , 183 Bovine ocular tissues Birch, D.G. , 313, 497 isolation of , 836 Bis-retinoid precursors , 75 PSG2 antibody , 838–839 Bisretinoids, RPE lipofuscin SDS-PAGE , 836–837 A2-DHP-PE , 764–765 S-IRPEM vs. IS-IRPEM , 838, 839 all- trans -retinal dimer vs.all-trans -retinal Western blot analysis , 837–838 dimer PE , 763–764 Bowles, K.E. , 505 biosynthetic pathways , 761–762 Bowne, S.J. , 313 photooxidation , 765 Braunger, B.M. , 679 Blacque, O.E. , 433 Bredberg, D.L. , 590 Blanks, J. , 269 Bright-fi eld macroscopic imaging , 480 Blast-like alignment tool (BLAT) , 522, 523 Brij 96 , 770 Blood-retinal barrier (BRB) Brn-3 genes , 686–687 Claudin-5 siRNA , 156–157 Brombas, A. , 807 iBRB modulation , 158–159 Bruban, J. , 67 846 Index

Bruch’s membrane (BM) , 12, 725, 765 TOR kinase , 208 Brush, R.S. , 553 Cellular homeostasis , 83 BTC. See Betacellulin (BTC) Cellular retinaldehyde-binding protein Bulls’s eye maculopathy , 454, 455 (CRALBP) Büning, H. , 183 11- cis -retinal Butler, M.C. , 145 illumination , 590 BVMD. See Best vitelliform macular photoisomerization , 592–593 dystrophy (BVMD) expression, purifi cation, crystallization , 590 ligand-binding cavity , 592 structure determination , 590–592 C Ceramide kinase like ( CERKL ) gene , 555 Caberoy, N.B. , 693 Ceramide signaling Cacna1f gene , 739 apoptotic cell death , 554 Caenorhabditis elegans , BBS proteins bioactive sphingolipids , 553 cellular functions , 534 Cer production , 554 IFT transport , 534–535 photoreceptor apoptosis , 554–556 nephronophthisis , 534 RPE cell death , 556 photoreceptor degeneration , 536–537 Cerebral neurodegenerative disease , 65 phototransduction , 536 Cer-induced RPE apoptosis , 556 pleiotropic disorder , 533 CFF. See Critical fl icker frequency primary cilium , 534 Chakraborty, D. , 633, 657 RPE cells , 535 Chalmers, K.J. , 367 Cai, J. , 83 Chang, B. , 130 Cai, X. , 245 Chavali, V.R.M. , 225 Calof, A.L. , 671 Cheetham, M.E. , 527, 595 Calpain and photoreceptor apoptosis Chemical cross-linking age-related macular degeneration , 547 amino-specifi c cross-linker BS3 , 770 barrier modulation , 551 with infrared fl uorescence detection , blood retina barrier , 549 772, 774 calpain activation , 548–549 Nrl−/−retina membrane , 770 calpain inhibitors , 549 protein complex evaluation , 772 caspase 8 , 548 Chemical mutagenesis , 400 transgenic mouse models , 549 Chemotactic cytokines , 39 Campbell, M. , 155, 547, 567 Chen, H. , 553 Canine-specifi c TaqMan assay , 361 Chiang, W.-C. , 559 Carboxy-ethyl-pyrrole (CEP) , 13 Choroidal neovascularization (CNV) , 4, 254 Carroll, J. , 451 CCR3 Caspase 8 , 548 animals and subretinal Matrigel Caspase-dependent apoptosis , 5 injection , 280 Castañeda, M.M. , 101 antagonist SB328437 effects , 281–283 Cav1.4 a 1 subunit blood vessels and measurement , 280 Cacna1f gene , 739 Matrigel model , 280–281 knockout mice , 740 role of , 279 loss of , 742 constitutive vs. regulated expression , Cdc42 , 583 270–271 Cell death endostatin effectiveness , 273–274 autophagosome , 208 hypoxia-regulated expression , 272–273 characterisation , 207 RPE-specifi c promotors , 271–272 future aspects , 212 Choroidal vascular development inherited retinal dystrophies , 209–210 animal experiments , 300 macroautophagy , 208 choroidal vessels , 303 mammalian autophagy , 208 quantifi cation , 300–301 pathway blockage , 211–212 retinal integrity , 301 retinal damage models , 210–211 RPE-produced VEGF , 301 Index 847

Choroideremia (CHM) Cone photoreceptors affected family members , 383 ROM-1 protein clinical characteristics , 383 electron microscopy , 635 confocal microscopy , 382–383 electroretinography , 634–635 E. coli particles , 383 gel electrophoresis and western blot FACS analysis , 382–383 analysis , 634 gene replacement , 386 ROM-1 overexpression, cone function lysosome-mediated degradation , 386 and structure , 635–637 patient population , 382 ROM-1 protein expression, transgenic proteolytic degradation , 385 mice , 635, 636 traffi cking defects , 386 transgenic mice generation , 634 Chow, A.Y. , 115 Cone–rod dystrophy (CRD) , 321, 497 Chrenek, M.A. , 641 Congenital stationary night blindness Chromatin immunoprecipitation (ChIP) , 754 clinical phenotype , 377 Chromatin signatures , 756–757 clinical variability , 375–376 Chromosome 10q26 susceptibility ERG features , 377 ARMS2 , 369–370 genetic analysis , 372 genetic association , 368–369 CACNA1F mutations , 373 Ciavatta, V.T. , 115 GRM6 mutations , 374 Ciliary neurotrophic factor (CNTF) NYX mutations , 374 adaptive optics scanning laser TRMP1 mutations , 374 ophthalmoscopy , 98 X-linked CSNB , 375 cone degeneration , 94 negative bright fl ash ERG , 377 COS regeneration , 96–97 , 377 light-sensing function , 97 statistical Analysis , 372 loss of cones , 95 strabismus , 377 loss of COS progress , 94–95 subjects , 372 PNA-negative areas , 96 Conley, S.M. , 633, 657 retinal degeneration , 94 Connor, T.B. Jr. , 451 S334ter rats , 94 Coomassie blue staining , 773 Ciliopathy , 318 Corbo, J.C. , 757 Circadian rhythms , 718 Cotter, T.G. , 549 cmr 2 mutant , 613, 614 C1q tumor necrosis factor-5 (C1QTNF5/ CNGA3 CTRP 5) , 225, 226 achromatopsia , 183 Craft, C.M. , 253, 791 electrophysiological analysis , 184 CRALBP. See Cellular retinaldehyde-binding ERG measurements , 186 protein (CRALBP) ganglion cells activation , 187 Cremers, F.P.M. , 345 immunohistochemistry , 185 Critical fl icker frequency (CFF) mouse expression , 185 ERG protocol , 506–507 photoreceptor function , 185–186 ISCEV standard tests , 506 rAAV vectors and injection , 184 photopic , 508–510 retinal cone-mediated signaling , scotopic , 507–508 187–188 Cronin, T. , 129 water habituation , 185 Crouch, R.K. , 75 CNV. See Choroidal neovascularization CRX (CNV) photoreceptor terminal Coat’s disease , 680 determination , 757 Cochran’s t -test , 643 retinal development, vsx2 , 675 Colley, N.J. , 407 Cubilla, M.A. , 101 Collin, R.W.J. , 345 Cutler, A. , 293 . See OPN1LW and OPN1MW Cyclic guanosine monophosphate (cGMP) cone gene channel Cone opsin promoter (COP-T) , 659 light adaptation , 781 848 Index

Cyclic guanosine monophosphate (cGMP) Diabetes, betacellulin , 295 channel (cont.) Diabetic retinopathy , 293 N-erminal and C-terminal region , 778 neovascular ocular diseases , 246 phototransduction , 781 pericyte injury , 285 subunits , 777 retinal neovascular disorders , 254 Cyclic nucleotide-gated (CNG) channels Dickkopf (DKK)-1, inhibitor , 681 cell culture studies and vectors , 778 Dinet, V. , 67 cone Ding, X.-Q. , 633, 769 blue native-PAGE , 770 Dlx genes , 687–688 chemical cross-linking , 770, 772 DNA microarray , 620 infrared fl uorescence Western Dodecylmaltoside (DDM) , 770 detection , 770 Donovan, M. , 549 stoichiometry of , 773–774 Dorey, C.K. , 269 subunits , 769 Double-stranded RNA (dsRNA) , 4 PHLPP1 and PHLPP2 Drosophila photoreceptor degeneration , 556 modulatory properties, lack of , Dryja, T.P. , 411 780–781 Dunn, W.A. Jr. , 83 RA domain assessment , 779–780 Dwyer, M. , 51 RA/RBD domain-containing proteins , 778 rods , 769 sequence alignment and domain assess- E ment , 778 Ebenezer, E.D. , 595 statistical methods , 778 Ebert, S. , 619 visual and olfactory transduction , 777–778 Ectonucleoside triphosphate diphosphydro- Cystosolic protein cone arrestin (CAR) , 659 lases (E-NTPDases) , 814 Eisenstat, D.D. , 685 Elastokines , 64 D Electroretinogram (ERG) , 506–510, 823 Dahrouj, M. , 23 Arr1 −/− mice , 793 Daiger, S.P. , 313 autosomal dominant retinitis pigmentosa , Dalal, N. , 641 200–201 Dark-adapted rod electroretinogram , 497 photopic CFF , 508–510 Dark-rearing rd 10 mouse protocol , 506–507 candidate retinal genes , 132 retinal photoresponses, HCN1−/−mice , 809 C57Bl/6J , 130 ROM-1 overexpression , 634–635 electroretinogram , 130–131 scotopic CFF , 507–508 immunohistochemical analysis , 132 small interfering RNA , 217 immunolabeling , 131 standard ISCEV fl icker test , 506, 510 LR-rd10 mice , 133, 134 translational vision research models phosphodiesterase 6b mutation , 129 program , 392 P23H-3 transgenic mouse , 133 Endogenously expressed bestrophin-1 , 605 PNM3 , 131–132 Endoplasmic reticulum , 289, 290, 607, 608 QrtPCR analysis , 131 Endoplasmic reticulum-associated degradation retinal gene expression , 135 (ERAD) rod function , 134 cytosolic events , 561–562 RTPCR , 129 dislocation , 560–561 Dean, M. , 368 glucosidase activition , 559 De Laurenzi, V. , 732 misfolded proteins recognition , 560 Dendritic cells (DCs) , 12 P23H , 562–563 den Hollander, A.I. , 345 protein-folding cycle , 560 Desiderio, D.M. , 11 quality control , 559 Devery, S. , 595 Endostatin , 273–274 Dexamethasone (DEX) , 101, 105 Endotoxin-induced autoimmune uveitis Dhubhghaill, S.N. , 155 (EAU) , 20 Index 849

Enhanced S cone syndrome (ESCS) , 823 Fong, W.G. , 207 ENU mutagenesis. See N-ethyl- N -nitrosourea Fourier transforms (FFTs) , 507 (ENU) mutagenesis Fritsche, L.G. , 369 Epidermal growth factor (EGF) , 294 Frizzled 4 (Fzd-4) , 681 Epidermal growth factor receptor (EGFR) , 830 Fujikawa, C. , 663 Epitope-tagged PEDF-R expression , 800 Fukada, 823 ERG. See Electroretinogram (ERG) Erythropoietin (Epo) , 138 glycosylation analogs , 141 G overexpression , 140 Ganglion cell functions , 476 retinal protection , 140 Ganglion cell layer (GCL) , 675, 687 External limiting membrane (ELM) , 454 Gardner, C. , 641 Extracellular matrix (ECM) , 370, 838 Gardner, J.C. , 595 Eye development , 399–400 Geisert, E.E. , 649 Gel electrophoresis , 634 Gene expression, retinal injury F in adult rats , 649 Factor XIIIA, Goldfi sh bioinformatic analyses , 651, 653–654 cDNA clone , 449 in fl d mice , 655 cloning , 446 network modulation , 651–653 gene expression change , 447–448 online databases , 651, 653–654 induced neurite outgrowth , 448 patterns of , 650 transglutaminase (TG) , 445 Gene fad mutant , 441 AAV-mediated , 239 Fahim, A.T. , 313 AMD , 270 Fahl, E. , 183 HRE , 272 Familial exudative vitreoretinopathy lentivirus-mediated gene therapy , 237–239 (FEVR) , 680 RDS/peripherin disease. , 216 Familial (Mendelian) maculopathies , 62 Genini, S. , 353 Fariss, R.N. , 661 Genome-wide occupancy analysis Farkas, M.H. , 519 ChIP-chip and ChIP-Seq Farrar, G.J. , 567 ChIPed DNA , 755 Fat-liver dystrophy (fl d) mouse , 655 NGS platforms , 755–756 Faulkner, A.E , 115 in vivo protein-DNA interactions , 754 Fenretinide transcription regulatory network amine analog , 172 histone modifi cations , 756–757 BCMO1 inhibitor , 169–170 transcription factor , 756 BSG1 enzyme , 168 Gentleman, S. , 167 cancer treatment , 167 Gerling, I.C. , 11 catalytic activation , 170, 172 Glaucoma , 655, 816 constructs , 168 Glucocorticoid-dependent mechanisms HPLC analysis, retinoid and carotenoids , 168 balb-c male mice , 102 molecular docking , 169 caspase-3 activation , 103–104 noncompetitive inhibition behavior, 170, 171 DEX , 101, 105 protein expression and enzyme assay , 168 GR a immunoreactivity , 104 RBP4 , 167 light-exposed retinas , 102–103 synthesis , 168–169 mifepristone , 101, 105 tertiary structure modeling , 169 mineralocorticoid receptor , 105 Fibroblast growth factors (FGFs) , 302 OS damage , 105 Finnemann, S.C. , 709, 731 rhodopsin , 103 Fischer, M.D. , 183, 491 Gobbo, O.L. , 155 Flatmount technique , 642 Godara, P. , 451 Fletcher, E.L. , 813, 816 Gollisch, T. , 183 Focal adhesion kinase (FAK) , 719 Gonzàlez-Duarte, R. , 329 850 Index

Gorbatyuk, M.S. , 191, 199, 569 HCN1 channels Gorbatyuk, O.S. , 191 HCN1−/−mice , retina G-protein-coupled receptor (GPCR) , 18, 793 fl icker fusion frequency , 810, 811 G protein-coupled receptor kinase (GRK) single-fl ash ERG response , 808–809 in changing light conditions, regulation of , knockout mice , 807 823–824 photoreceptor expression of , 822 mechanism in , 808 function of , 822–823 shaping and shortening , 807 photoreceptor, distribution in , 822 HDAC I/II inhibitors , 109 retinopathy, role in , 821 HDAC inhibition, Rd1 mouse Grant, G.R. , 519 C3H wild-type mice , 108 Grant, M.B. , 83 HDAC assay , 108 Graphpad Prism software , 778 histone modifi cations , 107 Greferath, U. , 813 molecular cell death pathways , 112 Gregory-Evans, C.Y. , 399 PARP activity , 109–110 Grey, A.C. , 75 death , 108 Griciuc, A. , 415 rd1 photoreceptors , 111 Grimm, C. , 491, 581 rd1 retina , 109 Grossman, G.H. , 293, 701, 783 rhodopsin , 111 Grossniklaus, H. , 641 TUNEL and immunostaining , 109 Growth and differentiation factor 11 (GDF11) in vitro retinal explant cultures , 108 olfactory epithelium (OE) , 672 Heat shock proteins (HSPs) , 567 retinal ganglion cells , 672 heat shock factor-1 , 663 retinal neurogenesis, negative regulator role , 663 of , 672 Hedstrom, L. , 539 signaling molecule , 672 Heintzman, N.D. , 757 transcription factor, role in , 673 Héon, E. , 533 Vsx2orJ/orJ mouse retina Hereditary retinal degeneration , 93 animal model , 673 He, X. , 589 epithelial thickness and cell Heynen, S.R. , 581 lamination , 674 Hicks, W. , 391 gene expression , 675 Hindges, R. , 671 histology and in situ hybridization , 673 Holder, G.E. , 595 rescued expression , 674 Hollyfi eld, J.G. , 459, 479 retinal development, restoration of , 675 Homeobox genes Growth factor receptor-bound protein 14 Brn-3 genes , 686–687 (Grb14) , 778 Dlx genes , 687–688 Gubin, A. , 167 islet genes , 689 Gu, J. , 15 Vax genes , 688 Guo, D.C. , 315 Homeodomain (HD) , 686 Gupta, V.K. , 777, 829 Homozygosity mapping Gutierrez, D.B. , 75 autosomal recessive disease , 346 Guziewicz, KE. , 611 consanguineous vs. nonconsanguineous families ABCA4 mutation , 348 H arCRD cohorts , 349 Hagstrom, S.A. , 701, 783 arRP genes , 348 Hamilton, J.A. , 671 retinal dystrophy genes , 349 Hamilton, R.A. , 835 schematic representation , 347 Hammerhead ribozyme (hhRz) , 147 future aspects , 350 Hanrahan, F. , 155 population composition , 349 Hao, H. , 753 single nucleotide polymorphisms , 346 Hardcastle, A.J. , 527, 595 strengths and limitations , 350 Hauswirth, W.W. , 191, 199, 215 Hood, D.C. , 497 Index 851

Hoppe, G. , 701 mouse retinal membrane protein , 770 Horner, T.J. , 823 Nrl −/− retina , 770 Huang, D. , 93, 279 Ingenuity pathway analysis (IPA) , 360 Huang, S.-P. , 791 Inner blood retina barrier (iBRB) , 550 Huber, G. , 183, 491 Inner plexiform layer (IPL) , 704 Human bestrophinopathy , 615 Inosine 5 ¢-monophosphate dehydrogenase Human postmortem eyes (IMPDH1) , 539

AMD retina , 483–485 Inositol 1,4,5-triphosphate (InsP3 ) , 720 bright-fi eld macroscopic imaging , 480 Institutional Animal Care and Use Committee macular hole , 482, 483 of the Cleveland Clinic , 702 normal retina , 481–482 Insulin receptor (IR) signaling OCT , 481, 487 and PTP1B RPE detachment , 482–484 in diabetes , 831 RP retina , 484–486 interaction between , 830–831 SLO , 480–481 in retina , 830 tissue preparation , 480 Intracellular traffi cking genes in vivo imaging , 485–487 intrafl agellar transport , 438–439 Human retinal gene (HRG) , 529 membrane transport , 440 Human retinal pericytes microtubule-dependent molecular motor , 439 activating transcription factor 4 , 287–289 Intrafl agellar transport (IFT) , 438–439, 529 C/EBP homologous protein , 287–289 IRDye-680 fl uorescence dye , 770 cell culture , 286 Ishikawa, Y. , 305 ER stress inhibition , 289, 290 Islet genes , 689 glucose fl uctuation , 285 glucose regulated protein (GRP78) , 287 macrophage chemoattractant protein 1 , J 285, 287 Jiang, Y. , 641 materials , 286 Jin, H. , 535 statistical analysis , 287 Jobling, A.I. , 813 western blot analysis , 286 Humphries, M.M. , 155, 547, 567 Humphries, P. , 155, 491, 547, 567 K Hyde, D.R. , 427 Kanan, Y. , 835 Hydroquinone (HQ) , 27 Kanda, A. , 369 4-Hydroxy(phenyl) retinamide (4-HPR). See Kang, M.J. , 420 Fenretinide Kanuga, N. , 595 Hyperoxia , 33–34 Kato, S. , 161, 445, 663 Hypoxia-regulated expression , 272–273 Kaul, C. , 459 Hypoxia-response elements (HREs) , 272 Kauper, K. , 93 Kawamura, S. , 823 Keaney, J. , 567 I Kenna, P.F. , 155, 547, 567 Iannaccone, A. , 11 Kennedy, B.N. , 433 IFT. See Intrafl agellar transport (IFT) Kiang, A.-S. , 155, 547, 567 Illumina platform , 755 Kim, M.K. , 115 Immunomics , 15 Kitiratschky, V. , 337 Induced pluripotent stem (iPS) cells , 523 Kleinman, M.E. , 3 Infrared fl uorescence Western detection Knockdown technology , 401 cone CNG channel Knockout mouse models , 516 advantages of , 774 Koch, S. , 183 blue native-PAGE, analysis by , 773 Kohl, S. , 337 chemicalc cross-linking , 772–773 Kolniak, T.A. , 145 CNGA3 and CNGB3, simultaneous Komori, N. , 769 detection of , 771 Koriyama, Y. , 161 852 Index

Kortvely, E. , 61, 369 accumulation , 86 Kraft, T.W. , 503, 505 late endo-lysosome, RPE , 725 Krishnamoorthy, V. , 183 in RPE Krishnamurthy, P. , 11 amino acid analysis , 761–762 Krizaj, D. , 739 bisretinoids ( see Bisretinoids, RPE Kroeger, H. , 559 lipofuscin) Kumasaka, N. , 305 Littink, K.W. , 345 Kunchithapautham, K. , 23 Liu, J. , 536 Kurtenbach, A. , 471 Li, W. , 693 Kuznetsova, T. , 321 Li, Y. , 93, 279 Lobsiger, J. , 589 Local vs. systemic mononuclear phagocytes L CCR2 and CX3CR1 signalling , 19–20 Laird, J. , 167 cellular innate immune system , 21 Lakkaraju, A. , 723 chemokine mouse model , 20 Langmann, T. , 619 chemokine receptor CX3CR1 , 19 Laser microdissection (LMD) , 703–704 CNV , 17 Late endosome–lysosome geographic atrophy , 17 cholesterol traffi cking , 723 microenvironment signals , 18 function and dysfunction , 724–725 myeloid cells , 19 health and disease , 727–728 reticular drusen , 21 protein–lipid sorting , 723 systemic and local innate immune cells , 18 in RPE , 725–726 Locke, K.G. , 497 signaling , 723 Lodha, N. , 371 Laties, A.M. , 93 Lohr, H.R. , 210 LaVail, M.M. , 93, 191, 215, 553 Lopes, V.S. , 235 Law, A.-L. , 717, 718 Loucks, C.M. , 371 LDL receptor-related protein (Lrp) , 680 Luhmann, U.F.O. , 17 Leber congenital amaurosis (LCA) , 177, 540 Luibl, V. , 68, 69 Lechtreck, K.F. , 535 Luo, L. , 93, 279 Lenchik, N.I. , 11 Lutein/zeaxanthin supplementation Lentivirus-mediated gene therapy , 237–239 ARPE-19 cells , 45 Lewin, A.S. , 191, 199, 215 C57BL mice , 47–48 Le, Y.Z. , 299 cell culture and treatment , 45 Li, F. , 129 dietary supplementation , 48 Light-damaged zebrafi sh retina experiments with animals , 44–45 induction of Müller glial proliferation , 429 immunoglobulin accumulation , 44 regeneration , 428–429 light-induced photoreceptor death , 44 Light-induced retinal degeneration, 34, 102–103 materials , 44 apoptotic cell death , 122 oxidative stress , 43 cone opsin gene regulation , 125 primary macrophage culture , 46–47 cone photoreceptor function , 122 pro-infl ammatory cytokines , 49 emerging therapeutic modality , 126 RPE , 45–46 gfap and fgf genes , 122 visual loss protection , 43 histopathological changes , 126 Lysosomes , 85 gene expression , 127 Lyubarsky, A. , 129, 131 OS, photic injury , 123–125 photoreceptor cell death , 123 postcon retinas , 127 M retinal dystrophies , 121 MacDonald, I.M. , 381 retinal function, photic injury , 125–126 Macroautophagy , 83, 208 Lin, J.H. , 191, 559 Macrophage chemoattractant protein 1 Lipid storage disease , 555 (MCP-1) , 285 Lipofuscin (LF) , 24, 75–76, 80, 85, 88 Macula lutea , 61 Index 853

Macular drusen , 452 Mifepristone (MFP) , 103, 105 Macular edema , 61 Mikkelsen, T.S. , 757 Macular hole , 482, 483 Milenkovic, V.M. , 603, 611, 616 Maculopathy Milewicz, D.M. , 315 extracellular matrix role , 65 Milk fat globule EGF-factor (MFG-E8) , macula lutea , 61 718–719 pathomechanisms , 64 Mitter, S.K. , 83 risk factors , 64–65 Mitton, K.P. , 758 shared protein networks , 62–63 Mok, C.A. , 533 Madin−Darby canine kidney Molday, L.L. , 795 (MDCK) cells Molecule-specifi c imaging and quantitation cell culture , 354, 359 A2E generation , 80 cellular viability assessment , 359 A2E oxidation sites , 78–79 Maher, A.R. , 595 bis-retinoid precursors , 75 Malek, G. , 51 LC-MS/MS-based technique , 80 Mandal, M.N.A , 553 lipofuscin accumulation , 75, 80 Mao, H. , 199 MALDI imaging , 76 Marfany, G. , 329 murine RPE , 77 Mascarelli, F. , 67 quantitation A2E , 77–78 Matrix-assisted laser desorption/ionization RPE tissue preparation , 76 (MALDI) , 76 Moore, A.T. , 595 Matsukawa, T. , 161 Moore, K.L. , 835 Matsumoto, H. , 769 Morphometrics analysis software , 646 Matthes, M.T. , 215, 553 Mowat, F.M. , 177 Matveev, A. , 769 Mühlfriedel, R. , 183 Ma, W. , 37 Müller, C. , 603 Mawatari, K. , 663 Müller cells, P2X7 receptor , 816–817 MBT. See Mushroom bodies tiny (MBT) Müller, F. , 807 McDonnell, D. , 51 Müller glia , 429, 430 McGinnis, J.F. , 245 Murine macrophages , 46–47 McGrew, D.A. , 539 Mushroom bodies tiny (MBT) , 582–583 Medaka fi sh , 822 Mutation in gene encoding, zebrafi sh Melanosomes , 238 intracellular traffi cking genes ( see Melino, G. , 732 Intracellular traffi cking genes) Membrane-associated protein cone transducin phototransduction protein , 435, 438 (GNAT2) , 659 structural factor , 440 Mer tyrosine kinase (MerTK) , 694 structural protein , 440 characterization of , 696–697 ligand study, phagocytosis RPE , 694 POS engagement , 719–720 N retinal degeneration , 693 Naash, M.I. , 633, 657 Michaelides, M. , 595 Nagai, N. , 305 Michalakis, S. , 183 Nagashima, M. , 663 Microglia Naggert, J.K. , 391 cellular interaction , 40 Nakashima, H. , 445 infl ammatory mediators and neurotrophic Nandrot, E.F. , 717, 718 agents , 37 Nanoceria , 250 legal blindness , 37 Nash, Z. , 633 maladaptive infl ammatory response , 38 Natoli, R. , 31 P2X7 receptor, retina , 817 Neeli, I. , 11 retinochoroidal interface , 38–39 Nelson, C.M. , 427 RPE interaction , 39–40 Neovascular ocular diseases Micro-ophthalmia , 671 age-related macular degeneration , 246 Microphotodiode arrays (MPA) , 115–120 animal models 854 Index

Neovascular ocular diseases (cont.) Norrin Akimba ( Ins2 Akita VEGF+/− ) mouse , 248 carboxyl-terminal -rich domain, 680 Akita ( Ins2 Akita+/− ) mouse , 248 disease choroidal neovascularization , 247 congenital X-linked recessive vascular endothelial growth disease , 680 factor , 247 missense mutations , 680 Vldlr gene , 247 NDP gene , 679 diabetic retinopathy , 246 symptoms , 680 oxygen induced retinopathy , 248 functions of , 682 retinopathy of prematurity , 246 in knock-in mouse model , 680 therapeutic treatment properties angiogenic pathways , 248–249 angiogenic , 681 , 249–250 neuroprotective , 681–682 regenerative medicine , 250–251 reproduction and development, role in , 682 targeting , 248–249 Neprilysin (NEP) , 68 N -ethylmaleimide sensitive factor (NSF) , 529 O ATPase activity , 793 OCT. See Optical coherence tomography domain structure , 792 (OCT) homo-hexameric member , 792 Odyssey® Infrared Imaging System , 770 photoreceptor Oguchi disease and Arrestin 1 (Arr1) (see Arrestin 1 GRK1 retinopathy , 821, 822 (Arr1)) in photoreceptor, NSF role , 796 protein traffi cking , 794–796 Ogun, O. , 595 SNAP–SNARE binding , 792–793 Ogunshola, O.O. , 581 N-ethyl- N -nitrosourea (ENU) mutagenesis , Oka, C. , 370 391, 400 Oligomeriztion-incompetent RDS Neural retina , 69–70, 85–86 C150S-RDS protein, mislocalization of , Neuronal progenitor cell proliferation , 657–658 429–430 rods and cones Neuroprotective dose response, RCS rats antibody and immunohistochemistry , ERG testing , 119 658 light dosing , 116–117 GNAT2 mislocalization, microphotodiodes , 115 COP-T/WT , 660 MPA device , 120 M-opsin and COP-T mislocalization, MPAs implantation , 116 COP-T/nrl−/− , 659–660 photoreceptor numbers , 117 transgenic mice , 658 photoreceptor survival , 118 transgenic mice , 657 retinal function , 117–118 Onami, H. , 305 retinal function testing , 117 Oogai, K. , 445 retinal preservation , 119 OPN1LW and OPN1MW cone opsin gene subretinal electrical stimulation , 116 cone dystrophy , 599 xenon fl ashes , 119 heterogeneous disorder , 595 Neurotrophic growth factors , 681 immunoblotting and immunocytochemistry, Neussert, R. , 603 596–597 Next generation sequencing (NGS) , 350, 755 missense mutation , 599 bioinformatic analysis , 522–523 molecular genetic analysis RNA-seq analyses , 523 array , 598 Nguyen, A.T.H. , 155, 547 gene-specifi c primer , 596 Nickerson, J.M. , 641 P23H treatment , 599 Niemann–Pick C1 protein , 728 RPGR mutation , 597 Nishina, P.M. , 391 W177R mutation , 598–599 N-methyl- D -aspartate (NMDA) injection , 681 ophthalmic assessment , 596 Noninvasive optical-biopsy , 479 phenotype , 597 Index 855

polymorphism , 600 MerTK ligand study , 694 retinitis pigmentosa , 599 ORF phage , 694, 695 Opn1mw gene expression , 127 signaling , 693 Optical coherence tomography (OCT) , Tulp1 −/− mice , 694 462–464, 466, 467, 479, 481 Phosphatidylethanolamine (PE) , 762 Optic nerve injury (ONI) , 663 3 ’ -Phosphoadenosine 5’ -phosphosulfate Optic nerve regeneration, gold fi sh (PAPS) , 835 animal care , 446 Phosphodiesterase 6B (PDE6B) , 641 factor XIIIA Phosphoinositol (PI) signaling , 416

cDNA clone , 449 Phospholipase A2 (PNPLA2) , 800 cloning , 446 Photic injury gene expression change , 447–448 OS , 123–125 induced neurite outgrowth , 448 retinal function , 125–126 transglutaminase (TG) , 445 Photopic critical fl icker frequency , 508–510 optic nerve transection , 449 Photoreceptor retinal explant culture , 447 apoptosis , 494, 554–556 in situ hybridization , 446 cAMP-dependent protein kinase , 824 wound healing , 445 cell death , 123 Optic nerve repair cells , 237 apoptosis , 165 ChIP-chip and ChIP-Seq, applications of , IGF-I , 162 757–758 mammalian CNS injury , 165 CNG channel ( see Cyclic nucleotide-gated neurite outgrowth-promoting factors , 162 (CNG) channels) nNOS , 163 cyclic AMP , 824 optic nerve regeneration process cytoskeleton , 583–584 stages , 161 degeneration and survival , 584 purpurin , 163–164 GRK1 and GRK7 (see G protein-coupled TG , 163 receptor kinase (GRK)) O’Riordan, C. , 573 HCN1 channel, mechanism of , 808 Osawa, S. , 821 N -ethylmaleimide sensitive factor ( see Ou, G. , 534 N -ethylmaleimide sensitive factor Outer nuclear layer (ONL) , 140, 142, 201 (NSF)) Outer plexiform layer (OPL) , 701 OS protein transport, tulp−/− retina Outer segment (OS) protein , 784 animal model , 784–785 Oxidative stress , 747–748 immunofl uorescent staining , 785 Oxygen induced retinopathy , 248 localization , 785 traffi cking , 786–787 survival, glucocorticoid-dependent P mechanisms (see Glucocorticoid- Papke, M. , 337 dependent mechanisms) Paquet-Durand, F. , 107, 491 Tulp1 complexes Parboosingh, J.S. , 371 crosslinked retinal samples , 705–706 Pardue, M.T. , 115 homogenization , 704 Pauer, G.J.T. , 701, 783 in IS and OPL , 702 pax6a gene , 430 isolation and capture of , 704–705 Peanut agglutinin (PNA) , 94 laser microdissection , 703–704 PEDF. See Pigment epithelium-derived factor retinal section preparation , 703 receptor (PEDF-R) tcTPC , 703 Penfold, P.L. , 12 Tulp1 −/− mice , 702–703 Peng, C. , 774 Wester blot analysis , 704, 705 Petersen-Jones, S.M. , 177 zebrafi sh Petrs-Silva, H. , 215 morphogenesis , 434–435 Phagocytosis, retinal pigment epithelium , 429 signifi cance , 433–434 functional character of , 698 vertebrate , 433 856 Index

Photoreceptor degeneration retina Caenorhabditis elegans , 536–537 distribution , 799 HDAC inhibition ( see HDAC inhibition, pnpla2 gene , 799 Rd1 mouse) RPE and photoreceptor , 799 Photoreceptor mosaic imaging. See Adaptive slot blot , 801 optics (AO) imaging Pinealocytes , 514 Photoreceptor neurons (PNs) , 415 Pinter, R. , 671 Photoreceptor outer segment (POS) , 693, 717, Plasma membrane Ca2+ ATPases (PMCAs) , 731, 745 740 Photoreceptor perisynaptic complex Platelet-derived growth factor receptor Cav1.4 a 1 subunit function , 740 (PDGFR) , 830

PMCA transporter and RIBEYE protein PNPLA2. See Phospholipase A2 (PNPLA2) animal model , 740 Poliakov, E. , 167 immunostaining , 740–741 Poly-ADP-ribosylated proteins (PAR) , 110 PMCA1 mislocalization , 741–742 Polyvinylidene fl uoride (PVDF) , 770 Phototransduction , 409–410 Pomares, E. , 329 cyclic nucleotide-gated channel , 769 Prentice, H. , 269 defects in , 832 Programmed cell death (PCD). See Cell death GPCR , 793 Proinfl ammatory cytokines , 40 GRK , 822 Protein misfolding protein interaction , 777 beta-sheet breakers , 569 P23H rhodopsin (RHO) photoreceptors chaperone activation , 569–570 BiP/Grp78 protein , 196–197 gene therapy , 570 control-injected eyes , 193 loss-of-function , 568 ERG , 193 mediating factors cell toxicity , 570 gene therapy , 196 nonproductive intermediates , 567 genetic modifi cations , 191 photoreceptor cells , 568–569 homozygous transgenic animals , 192 RDS-peripherin , 568 HSF1 expression , 195–196 rhodopsin , 569 human BiP/Grp78 expression , therapeutic strategies, toxicity , 569 193–194 Protein tyrosine- O -sulfation. See Sulfation immunohistochemistry , 192 Protein tyrosine phosphate-1B (PTP1B) mouse RHO 301 expression , 194 insulin receptor signaling retinal integrition , 194 interaction between , 830–831 traffi cking , 195 in retina , 830 transgenic rat , 196 nonreceptor PTP , 829 Pierce, E.A. , 519 retinal disease, activity in , 831 Pigment epithelium-derived factor RTK (PEDF) , 69 dephosphorylation and inactivation , 830 Pigment epithelium-derived factor receptor JAK/STAT pathway , 830 (PEDF-R) negative regulator , 829 antibody , 800 structure , 829 blocking peptides , 804–805 therapeutic target , 831–832 immuno-blot , 801 Provis, J. , 31 immunoreactivity PTGS agents rat retina R28 cell, as native , development , 146–147 803–804 expression and animal testing , 151 recombinant PEDF-R polypeptide , 802 hammerhead ribozyme , 147 synthetic peptides , 802–803 lead candidate identifi cation , 151 membrane fractionation , 801 lead candidate optimization , and PEDF interaction , 800 150–151 peptides and proteins , 800 siRNA , 148 phospholipase A activity , 800 Purpurin , 163–164 polyacrylamide gel electrophoresis , 801 Puthussery, T. , 816 Index 857

Q negative regulator , 829 Qin, S. , 745 Recombinant adeno-associated virus (rAAV) Qin, T. , 43 vector , 216, 218–219 Qi, X. , 83 Redmond, M. , 76 Quantitative reverse transcription-PCR Redmond, T.M. , 167, 491 (qRT-PCR) Remé, C. , 619 canine-specifi c TaqMan assay , Ren, Z. , 43 354–358 Retina experimental conditions , 361 ATP ( see Adenosine 5¢ -triphosphate MDCK cell (ATP)) cell culture , 354, 359 cholesterol , 726 cellular viability assessment , 359 function , 731 Quantitative trait locus (QTL) analysis , 651 HNC1 channels (see HCN1 channels) insulin receptor signaling in , 830 R photoreceptor outer segments , 693 RAC1 , 582–584 purine receptors , 814 Radic, M.Z. , 11 purinergic system , 813 RA domain-containing protein P2X7 receptor, role of cell culture , 778 microglial cells , 817 domain assessment , 778 Müller cell , 816–817 Grb14 , 781 neuronal degeneration , 815–816 IR signaling, role in , 778 neuronal modulation , 815 PHLPP1 and PHLPP2 vs. P2X receptor , 815 assessment of , 779 Retinal abnormalities, mice on CNG channel activity, effect of , abnormal pathology , 468 780–781 AFF , 464 sequence alignment , 778 animal model , 460–461 statistical methods , 778 histology , 462 vectors , 778 imaging procedures , 462 Rahman, A.K. , 553 noninvasive ocular imaging , 467 Rajala, A. , 777 retinal arteriole-venous malformation , 463 Rajala, R.V.S. , 777, 829 retinal morphology , 460 Ranchon-Cole, I. , 140 RPE , 462–463 Rao, H.V. , 83 SLO & OCT images , 464–467 Rapamycin , 27, 280 superior-temporal abnormality , 463 Rapp, M. , 799 visible fundus photography , 467 Rayborn, M.E. , 459 Retinal atrophy and visual loss , RCS rats implantation 454–456 photoreceptor survival , 119 Retinal cone-mediated signaling , retinal function , 117–118 187–188 Rd10 mice, retinal degeneration model Retinal degeneration , 138 autosomal recessive RP , 641 amyloid- b role ( see Amyloid-b role) cell shape , 643–642, 646 anticomplement strategy , 34 dramatic changes in , 643, 644 apoptotic cells , 34 fl atmount technique , 642 ceramide signaling (see Ceramide mean data , 643, 644 signaling) missense mutation, PDE6B , 641 Drosophila melanogaster morphometrics , 643, 645 ABCA4 gene , 408–409 Nikon C1 confocal imaging system , 643 compound eye , 409–410 ZO-1 staining , 642 genetic screening , 411 Receptor tyrosine kinase (RTK), PTP1B phototransduction , 409–410 dephosphorylation and inactivation , 830 red-eyed Vs. white-eyed , 408 JAK/STAT pathway , 830 retinitis pigmentosa , 409 858 Index

Retinal degeneration (cont.) homozygosity mapping spontaneous mutation , 407 autosomal recessive disease , 346 enzymatic cleavages , 31 consanguineous vs. nonconsanguineous gene association study , 32 families , 347–349 in human , 411–412 future aspects , 350 hyperoxia , 33–34 population composition , 349 MerTK phagocytic receptor , 693 single nucleotide polymorphisms , 346 pathogenic complement activation , 32 strengths and limitations , 350 photoreceptor injury , 33 indirect molecular diagnosis P23H-3 rodent , 33, 35 cosegregation SNP-Chips , 333 PTP1B activity , 831 homozygosity mapping , 332–333 Sprague Dawley (SD) rats , 32 optimized cost-effective multitiered zebrafi sh strategy , 333–334 drug discovery , 403 Retinal ganglion cell (RGC) , 161, 471 embryogenesis , 399 growth and differentiation factor 11 , 672 functional assessment , 401–402 norrin-defi cient mice , 681 genetic resources , 400–401 transcription factors , 686 morphological and embryological Brn-3 genes , 686–687 features , 399–400 Dlx genes , 687–688 Retinal degeneration slow (RDS) islet genes , 689 mutation in , 657 Vax genes , 688 rod and cone outer segment biogenesis, 657 Retinal gene expression , 135 rods and cones Retinal injury C150S-RDS expression , 636–637 in adult rats , 649 disc rim formation , 636 bioinformatic analyses , 651, 653–654 OS morphogenesis , 636 in fl d mice , 655 and ROM-1 protein, 633, 636–638 (see network modulation , 651–653 also Rod outer segment membrane online databases , 651, 653–654 protein-1) patterns of , 650 Retinal degenerative disease (RDD) Retinal ischemia , 211 clinical examinations , 498 Retinal light damage dark-adapted rod amplitude , 500–502 anemia , 138 gene therapy , 152 aranesp/AMG114 , 138, 139 human clinical translation , 151 Epo expression , 140, 141 lead candidate identifi cation , 150 Epo glycosylation analogs , 141 lead candidate optimization , 150–151 ERG amplitudes , 140, 141 mRNA expression , 148 intravitreal injections , 139 mRNA structure determinations , 148–149 light-induced cell death , 138 pair-fl ash ERG results , 498 nonhematopoietic cells , 141 PTGS agents , 147–148 ONL thickness , 140, 142 PTGS development , 146–147 outer nuclear layer thickness , 140 PTGS expression and animal testing , 151 retinal degenerations , 138 rod inactivation kinetics evaluation, 498–499 Retinal neovascular disorders (RNV) rod photoresponse recovery kinetics , age-related macular degeneration , 255 499–500 neovascularization

T sat correlation , 500–502 genetic mouse models , 255–256 Retinal dystrophies , 519 nongenetic models , 256–257 Bothnia-type (see Bothnia-type retinal preclinical drug testing , 257 dystrophy) proliferative diabetic retinopathy , 254 direct molecular diagnosis retinopathy of prematurity , 254 mutation screening chips , 330, 331 Retinal nerve fi bre layer (RNFL) , 474 next-generation sequencing , 332 Retinal pigment epithelial (RPE) cells, 452, 454, resquencing chips , 330, 332 462–463, 520–521, 535, 604–606 future aspects , 334 antimycin A treatment , 27 Index 859

ARPE-19 , 24–25 wild type vs. b 5−/−eyecups , 711–712 bevacizumab , 28 vascular endothelial cell expression , 25 blood vessel growth , 27 VEGF-R2 receptor , 26 CD55 and CD59 inhibitors , 25, 26 zona occludens 1, tight junction cell-cell contact , 641 molecule , 641 CNV , 24 Retinal pigment epithelial (RPE) cells dendritic cell , 731, 735 autophagy , 86–87 endo-lysosome network , 723–724 Retinal pigment epithelium (RPE) FAK and MerTK, receptor activities , AMPK 719–720 allosterical activation , 746 glycoprotein secretion , 731 cell barrier function , 747–748 internalization , 720–721 cell infl ammatory response , 748–749 late endosome–lysosome (see Late cell survival , 749 endosome–lysosome) cellular process, role in , 746 macrophages , 731, 735 inactivation , 747 macula , 23 phagocytosis , 748 melanosomes , 237 Ser/Thr kinase , 746 morphometrics , 643, 645 subunit , 746 MYO7A gene , 236 via Thr 172 Pphosphorylation , 746–747 oxidative stress , 24 cell signaling modifi cation , 745–746 pattern and cell shape of , 642, 643 chronic oxidative stress , 745 phagocytosis drusen biogenesis and AMD functional character of , 698 pathogenesis , 745 MerTK ligand study , 694 functions , 745 ORF phage , 694, 695 location of , 745 signaling , 693 Retinal pigment epithelium (RPE) lipofuscin Tulp1 −/− mice , 694 A2E , 763 PR phagocytic machinery, molecules of bisretinoid animal models , 718 A2-DHP-PE , 764–765 “eat me” signal , 718 all- trans -retinal dimer vs.all-trans - milk fat globule EGF-factor , 718–719 retinal dimer PE , 763–764 phosphatidylserine , 718 biosynthetic pathways , 761–762 ranibizumab , 28 photooxidation , 765 rapamycin , 27 Retinal vascular permeability. See Betacellulin rd 10 mice (BTC) autosomal recessive RP , 641 Retinitis pigmentosa (RP) , 107, 209, 409, 497, fl atmount technique , 642 584, 599, 781 mean data , 643, 644 adRP , 519 missense mutation, PDE6B , 641 BCVA , 472 Nikon C1 confocal imaging system, 643 characteristics , 783 ZO-1 staining , 642 cohort study , 474 RPE layer , 38 electrophysiological recordings , 472–473 shed POS , 709 ERAD , 562–563 synchronized diurnal phagocytosis, rod ganglion cell functions , 476 POS , 735 heterogeneous inherited retinal disorder, 701 transglutaminase-2 IMPDH1-linked animal and tissue collection , 710, 732 characterization , 539 histology , 733 enzymatic properties , 540 immunoblotting , 711 IMPDH and retina , 540 immunofl uorescence microscopy , 711 IMPDH structure and function , localization and expression , 712–713 540–541 POS phagosome quantifi cation , 733 retinal splice variants , 541–542 TG2−/− mice (see Transglutaminase-2 rhodopsin mutations , 539 (TG2)) translation regulation , 542–543 860 Index

Retinitis pigmentosa (RP) (cont.) animal models , 200 inner retina structure-function relation , 475 electroretinography , 200–201 next-generation sequencing (NGS) , Drosophila bioinformatic analysis , 522–523 abnormalities in phototransduction , 418 RNA-seq analyses , 523 maturation, traffi cking and proteasomal pathophysiological processes , 477 clearance , 419–420 in photoreceptor, NSF role , 796 mutations , 416–417 photoreceptors death , 477 PNs , 415 pre mRNA processing factor mutation , 520 programmed cell death , 420 Prpf31 -knockout animals , 520 Rh1 endocytosis and autophagy , rd 10, autosomal recessive model , 641 418–419 retinal disorder , 783 PTP1B activity , 831 retinal nerve fi bre layer imaging , 474 RHO301 gene cloning , 200 RGC morphology , 471 translational vision research models pro- RNA splicing factor mutant mice , 523 gram , 395–396 RP diagnosis , 472 Rho GTPases RPE degenration , 520, 521 activation , 581–582 SMA , 520 overlapping function , 582 SMN1 mutations , 521 photoreceptor Retinitis pigmentosa GTPase regulator cytoskeleton , 583–584 (RPGR) degeneration and survival , 584 candidate modifi er genes , 314, 315 retinal development , 582–583 clinical diversity , 314 Ribbon synapses , 739 data analysis , 315–316 Rinner, O. , 823 modifi er SNPs , 316–317 Ripamonti, C. , 595 phenotypic heterogeneity , 316 Ritter, M.R. , 251 protein transport , 314 Rivera, A. , 368 Retinitis pigmentosa protein (RP2) RNV. See Retinal neovascular disorders (RNV) Chlamydomonas protein , 528 Robson, A.G. , 595 cilia localisation and function , 528–529 Rod inactivation kinetics evaluation , 498–499 interaction partners , 529–530 Rod ON-bipolar cells (RBCs) , 130 mutations , 527 Rod opsin retinitis pigmentosa TBCC , 527–528 autophagy , 577–579 Trypanosome protein , 528 characteristics , 573 UNC119 , 529 gene expression analysis , 574–575 vesicle traffi c , 528 immunofl uorescence , 574 Retinol-binding protein (RBP4) , 167 intracellular traffi cking , 575 Retinopathy of prematurity (ROP) P23H rhodopsin , 576, 577 NDP mutations , 680 protein misfolding disease , 573 neovascular ocular diseases , 246 TUNEL assay detection , 574 retinal neovascular disorders , 254 UPR activation , 575 Retinoschisin (RS1) vectors expression , 574 , 515–516 western blotting , 574 gene therapy , 516–517 wild-type opsin , 577–578 molecular pathology , 516 Rod outer segment membrane protein-1 (ROM-1) RS1 gene and protein , 514 electron microscopy , 635 X-linked retinoschisis mutations , 515 electroretinography , 634–635 Reverse tetracycline transactivator (rtTA) , 255 gel electrophoresis and western blot Rex, T.S. , 140 analysis , 634 Reynolds, A.L. , 433 ROM-1 overexpression, cone function and Rha, J. , 451 structure , 635–637 RHO. See Rhodopsin (RHO) ROM-1 protein expression, transgenic Rhodopsin (RHO) , 103 mice , 635, 636 AAV gene delivery , 201–203 transgenic mice generation , 634 Index 861

Rohrer, B. , 23, 34 Shang, F. , 43 Rotstein, N.P. , 557 Shared protein networks, maculopathy , 62–63 RPE. See Retinal pigment epithelium (RPE) Shi, L.Y. , 391 Rpe65-defi ciency Sieving, P.A. , 513 AAV , 180 Silvin, C. , 381 Briard dogs , 177–178 Singh, A. , 769 eye treatment , 180 siRNA. See Small interfering ribonucleic acid gene therapy (siRNA) phase I/II clinical trials , 179–180 Sliesoraityte, I. , 471 proof-of-principle trials , 179 SLO. See Scanning laser ophthalmoscopy (SLO) LCA , 177 Small interfering ribonucleic acid (siRNA) photoreceptor/cone degeneration , 178 cell culture , 226–227 therapeutic intervention , 179 CTRP5/ Ctrp5 expression , 230–231 treatment safety and effi cacy , 180 design , 226 RPGRIP1 ELOVL4 mRNA cilia assembly , 323–324 ELOVL4-GFP fusion protein , 228 cilia protein network , 322 protein expression , 227–228 ciliogenesis , 324 quantitative RT-PCR analysis , 229 cytoskeleton dynamic regulation , 324 STGD3 , 229 expression , 322 wild-type ELOVL4 allele , 229 Ins44 mutation , 325–326 rds expression knockout studies , 322 AAV production , 217 molecular network components , 325 cell transfection , 216–217 retina , 322 combination therapy , 220–222 Ruggiero, L. , 709, 731 construction , 220 Rutar, M. , 31 electroretinogram , 217 Ryoo, H.D. , 420 HEK-293 cells , 218 rAAV-5 vector , 218–219 RNA isolation , 217 S semiquantitative real-time PCR , 217 Saadi, A. , 553 statistical analysis , 218 Saari, J.C. , 590 subretinal injection , 217 Salomon, R.G. , 167 transfection , 226–227 Sancho-Pelluz, J. , 107 transfection Cos-7 cells , 227 Santos, R. , 671 Smith, A.J. , 177 Sarang, Z. , 731 Smith, G.W. , 269 Sato, Y. , 305 Soluble interphotoreceptor matrix Sauer, A. , 337 (S-IPM) , 836 Scanning laser ophthalmoscopy (SLO) , Soluble interretinal pigment epithelium matrix 462–466, 479, 480 (S-IRPEM) , 836 Scaria, A. , 573 Song, A. , 573 Schaich, S. , 337 Sonoda, H. , 305 Schey, K.L. , 75 Sorsby, A. , 261 Schmidt, J. , 183 Sorsby fundus dystrophy (SFD) , 62 Schwarz, N. , 527 angiogenesis molecular mechanism , Scotopic critical fl icker frequency , 507–508 264–265 SD-OCT. See Spectral domain optical animal models , 264 coherence tomography clinical manifestations , 262 SDS polyacrylamide gel (SDS-PAGE) therapeutic intervention , 262 R28 cell, membrane fractions , 804 TIMP3 tissue lysate, Western blot of , 836 AMD , 265 Seeliger, M.W. , 183, 491, 807 molecular characteristics , 262 Sezate, S.A. , 245 mutation spectrum , 262 SFD. See Sorsby fundus dystrophy (SFD) Sparrow, J.R. , 726, 761 862 Index

Spectral domain optical coherence Tam, L.C.S. , 155, 547, 567 tomography (SD-OCT) Tamm, E.R. , 679 advantages , 491–492 Tanimoto, N. , 183, 807 C57BL/6 wild-type mice , 494–495 Tanito, M. , 129 focal light damage , 493 Tao, W. , 93 histological analysis , 492–493 Target of rapamycin (TOR) kinase , 208 photoreceptor apoptosis , 495 Thurman, J.M. , 23 rapid degenrative process , 493 Time-controlled transcardiac perfusion retinal imaging , 492 crosslinking (tcTPC) , 702 retinal structure, dynamic changes , 495 Timmers, A. , 200, 217 rod outer segments , 493 Toll-like receptor (TLR)-mediated cell Spinal muscular atrophy (SMA) , 520 response Sporadic maculopathy , 62 age-related macular degeneration (AMD) Stabila, P. , 93 caspase-dependent apoptosis , 5 Stanton, C.M. , 367 CNV , 4 Stargardt disease , 76, 167, 502 L412F gene , 4, 6 Stargardt-like macular degeneration (STGD3) , photoreceptor arrays , 5 229, 232 retinal pigment epithelium (RPE) , 5–6 Stat3 protein , 430 VEGF-A polymorphism , 6 Staurosporin , 359, 360 neuroimmunity , 3–4 Stepien, K.E. , 451 short interfering RNA (siRNA)-based Stocker, A. , 589 drugs , 6–7 Stockman, A. , 595 Tran, J.-T.A. , 553 Stöhr, H. , 261 Transcription factor (TF) Strau b , O. , 603 ChIP-chip and ChIP-Seq analysis , 756 Strunnikova, N. , 381 chromatin-remodeling activity , 753 Subramanian, P. , 799 distal enhancer , 753 Suburo, A.M. , 101 photoreceptor, role in , 757–758 Sugimoto, M. , 293 RGC cell, role in (see Retinal ganglion cell Sugitani, K. , 161, 445 (RGC)) Sugrue, A. , 83 Transferase dUTP nick end labeling Sulfation (TUNEL) , 109 bovine ocular tissues Transgenic mice isolation of , 836 b B1-crystallin norrin , 681 PSG2 antibody , 838–839 ROM-1, cone photoreceptors , 634 SDS-PAGE , 836–837 Transglutaminase-2 (TG2) S-IRPEM vs. IS-IRPEM , 838, 839 animal and tissue collection , 710 Western blot analysis , 837–838 av b 5 integrin-dependent phagocytosis , human coagulation factor VIII , 836 714 in multicellular eukaryotes , 835–836 b 1or b 3 coreceptor , 710 postranslational modifi cation , 835 immunoblotting , 711 protein function, modifi cation of , 835 immunofl uorescence microscopy , 711 in retina and RPE , 836 TG2−/− mice display signifi cance of , 836 morphology of , 733, 734 Sullivan, J.M. , 145 rod POS phagocytosis , 733–735 Sullivan, L.S. , 313 in vivo and immunoprecipitation Suzuki, M. , 155 studies , 732 Szondy, Z. , 731 wild-type, localization mouse retina , 712–713 rat RPE, primary culture , 713 T wild type vs. b 5−/−eyecups , 711–712 Tachibanaki, S. , 823 Transient receptor potential (TRP) , 409–410 Taggart, R.T. , 145 Translational vision research models program Takahashi, K. , 270 chemically induced mutants , 391 Index 863

clinical evaluation and electroretinography , V 392 Valter, K. , 31, 121 genetic mapping , 392 Vascular endothelial growth factor (VEGF) , histological analysis , 393 254, 279, 307 mice origins and husbandry , 392 Vasireddy, V. , 225 mutational analysis , 392 Vasohibin-1 Pde6a alleles , 393 corneal and retinal neovascularization , 309 rhodopsin mutation , 395–396 expression , 307 tubby-like protein 1 , 393–395 mRNA extraction , 306–307 Travis, G. , 76, 726 real-time polymerase chain reaction , 306–307 Triton X100 , 770 RPE Troeger, E. , 471 dynamics and proliferation , 307–309 TRP. See Transient receptor potential preparation , 306 (TRP) real-time RPE impedance analysis , 306 Tsilfi dis, C. , 207 vascular maturation processes , 309 Tubby-like protein 1 (Tulp1) , 393–395 western blot analysis , 307 C-terminal domain , 698 Vázquez-Chona, F.R. , 349, 650, 652–654 expression of , 783 Vessey, K.A. , 813 location , 701 Vijayasarathy, C. , 513 membrane vesicle preparation , 694, 695 Vinores, S.A. , 272 mutation in , 701 Visual system homeobox 2 (Vsx2) gene neuronal function , 783 failed retinal development , 671 phagocytosis ligand , 696 GDF11 levels ( see Growth and photoreceptor compartment differentiation factor 11 (GDF11)) crosslinked retinal samples , 705–706 micro-ophthalmia , 671 homogenization , 704 mutant mouse , 671–672 in IS and OPL , 702 isolation and capture of , 704–705 laser microdissection , 703–704 W retinal section preparation , 703 Wadsworth, S. , 573 tcTPC , 703 Wagner-Schuman, M. , 451 Tulp1 −/− mice , 702–703 Wakusawa, R. , 305 Wester blot analysis , 704, 705 Walczak, Y. , 619 receptor , 696–697 Walker, T.A. , 115 role , 784 Wang, G. , 369 Tulp1−/−mice, animal model Wang, J.J. , 285, 391 CO2 inhalation , 784 Wang, T. , 88 immunofl uorescent staining , 785 Wang, Z. , 279 Tubulin cofactor C (TBCC) , 527 Wan, H. , 11 Tyrosylprotein sulfotransferase Watson, R.F. , 783 (TPST) , 835 Webb, K.D. , 313 Webb, T.R. , 595 Weiss, E.R. , 821 U Wen, R. , 93, 279 Ueffi ng, M. , 61, 415 Wen, Y. , 497 Unfolded protein response (UPR) , 573 Western blot analysis Usher syndrome type 1B ROM-1 overexpression , 634 AAV-mediated gene therapy , 239 sulfation, bovine ocular tissues , 837–838 characterisation , 235 Tulp1, photoreceptor compartment , 704 lentivirus-mediated gene therapy , Wheaton, D.K. , 313 237–239 Wild type (WT) , 148 MYO7A gene , 236 Williams, D.S. , 235 Myo7a- mutant mice , 237, 238 Williams, J.T. , 313 strategies , 240 Wissinger, B. , 337 864 Index

Wittig, I. , 770 screening , 435 Wnt/ b -catenin signaling pathway structural factor , 440 DKK-1, inhibitor of , 681 structural protein , 440 neurotropic growth factors , 681 neuronal progenitor cell proliferation , Wong, W.T. , 37 429–430 Won, J. , 391 photoreceptor outer segment Wright, A.F. , 367 morphogenesis , 434–435 Wright, G.A. , 595 signifi cance , 433–434 Wu, D. , 43 vertebrate photoreceptors , 433 Wu, J. , 671 retina, HSP70 and HSF-1 animal model , 664 expression and localization, after ONI X and heat shock , 665–667 Xia, X. , 279 immunohistochemistry , 664 Xing, W. , 739 mRNA mechanism , 665, 666 X-linked cone dystrophy (XLCOD5). See in situ hybridization , 664–665 OPN1LW and OPN1MW cone tissue preparation , 664 opsin gene treatment , 664 X-linked inhibitor of apoptosis (XIAP) retinal degeneration protein , 211–212 drug discovery , 403 X-linked juvenile retinoschisis (XLRS) , 514 embryogenesis , 399 X-linked progressive retinal atrophy 2 functional assessment , 401–402 (XLPRA2) , 354 mitochondrial vertebrate , 400 X-linked retinitis pigmentosa , 314–315 morphological and embryological features , 399–400 mutant strain repository , 401 Y screen , 400–401 Yamamoto, K. , 761 ZGC , 400 Yang, H. , 553 retinal stem cell mutants , 441 Yasumura, D. , 215, 553 transcription factors for Müller Yau, E.H. , 145 glia , 430 Yetemian, R.M. , 253 Zebrafi sh Gene Collection (ZGC) , 400 Yu, M. , 553 Zein, W.M. , 381 Zhang, C. , 272 Zhang, Q. , 685 Z Zhang, S.X. , 285 Zangerl, B. , 321, 611 Zhao, C. , 792 Zebrafi sh Zhao, L. , 37 light-damaged retina model , 427 Zheng, L. , 299 induction of Müller glial proliferation , Zhong, H. , 773 429 Zhong, Y. , 285 regeneration , 428–429 Zhu, M. , 299 mutation in genes encoding Ziccardi, L. , 513 intracellular traffi cking genes ( see Zolotukhin, S. , 217 Intracellular traffi cking genes) Zong, X. , 183 phototransduction protein , 435, 438 Zrenner, E. , 471