Mouse model of ocular hypertension with retinal ganglion cell degeneration
Ocular hypertension is a primary risk factor for glaucoma and results in retinal ganglion cell (RGC) degeneration. Current animal models of glaucoma lack severe RGC cell death as seen in glaucoma, making assessment of physiological mediators of cell death difficult. We developed a modified mouse mod...
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creator | Mukai, Ryo Park, Dong Ho Okunuki, Yoko Hasegawa, Eiichi Klokman, Garrett Kim, Clifford B Krishnan, Anitha Gregory-Ksander, Meredith Husain, Deeba Miller, Joan W Connor, Kip M |
description | Ocular hypertension is a primary risk factor for glaucoma and results in retinal ganglion cell (RGC) degeneration. Current animal models of glaucoma lack severe RGC cell death as seen in glaucoma, making assessment of physiological mediators of cell death difficult. We developed a modified mouse model of ocular hypertension whereby long-lasting elevation of intraocular pressure (IOP) is achieved, resulting in significant reproducible damage to RGCs.
In this model, microbeads are mixed with hyaluronic acid and injected into the anterior chamber of C57BL/6J mice. The hyaluronic acid allows for a gradual release of microbeads, resulting in sustained blockage of Schlemm's canal. IOP elevation was bimodal during the course of the model's progression. The first peak occurred 1 hours after beads injection, with an IOP value of 44.69 ± 6.00 mmHg, and the second peak occurred 6-12 days post-induction, with an IOP value of 34.91 ± 5.21 mmHg. RGC damage was most severe in the peripheral retina, with a loss of 64.1% compared to that of untreated eyes, while the midperiphery exhibited a 32.4% loss, 4 weeks following disease induction.
These results suggest that sustained IOP elevation causes more RGC damage in the periphery than in the midperiphery of the retina. This model yields significant and reproducible RGC degeneration. |
doi_str_mv | 10.1371/journal.pone.0208713 |
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In this model, microbeads are mixed with hyaluronic acid and injected into the anterior chamber of C57BL/6J mice. The hyaluronic acid allows for a gradual release of microbeads, resulting in sustained blockage of Schlemm's canal. IOP elevation was bimodal during the course of the model's progression. The first peak occurred 1 hours after beads injection, with an IOP value of 44.69 ± 6.00 mmHg, and the second peak occurred 6-12 days post-induction, with an IOP value of 34.91 ± 5.21 mmHg. RGC damage was most severe in the peripheral retina, with a loss of 64.1% compared to that of untreated eyes, while the midperiphery exhibited a 32.4% loss, 4 weeks following disease induction.
These results suggest that sustained IOP elevation causes more RGC damage in the periphery than in the midperiphery of the retina. This model yields significant and reproducible RGC degeneration.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0208713</identifier><identifier>PMID: 30640920</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Acids ; Angiogenesis ; Animal models ; Animals ; Anterior chamber ; Automation ; Beads ; Biology and Life Sciences ; Blockage ; Cell cycle ; Cell death ; Complications and side effects ; Damage ; Degeneration ; Disease Models, Animal ; Eye (anatomy) ; Field study ; Glaucoma ; Glaucoma - metabolism ; Glaucoma - physiopathology ; Hyaluronic acid ; Hypertension ; Immunohistochemistry ; Intraocular pressure ; Intraocular Pressure - physiology ; Laboratory animals ; Laboratory rats ; Male ; Medical schools ; Medicine and Health Sciences ; Mice ; Mice, Inbred C57BL ; Microspheres ; Nanoparticles ; Ocular Hypertension - metabolism ; Ocular Hypertension - physiopathology ; Ophthalmology ; Physical Sciences ; Retina ; Retina - metabolism ; Retina - physiopathology ; Retinal Degeneration - metabolism ; Retinal Degeneration - physiopathology ; Retinal ganglion cells ; Retinal Ganglion Cells - metabolism ; Retinal Ganglion Cells - pathology ; Risk analysis ; Risk factors ; Tomography, Optical Coherence</subject><ispartof>PloS one, 2019-01, Vol.14 (1), p.e0208713-e0208713</ispartof><rights>COPYRIGHT 2019 Public Library of Science</rights><rights>2019 Mukai et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2019 Mukai et al 2019 Mukai et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-57d3ca38f757acb1d8403191ccfde737eb02746a079e4a1de42f2c256bfee2463</citedby><cites>FETCH-LOGICAL-c692t-57d3ca38f757acb1d8403191ccfde737eb02746a079e4a1de42f2c256bfee2463</cites><orcidid>0000-0003-1796-9232 ; 0000-0002-2048-9080</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6331128/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6331128/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,724,777,781,861,882,2096,2915,23847,27905,27906,53772,53774,79349,79350</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30640920$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Agudo-Barriuso, Marta</contributor><creatorcontrib>Mukai, Ryo</creatorcontrib><creatorcontrib>Park, Dong Ho</creatorcontrib><creatorcontrib>Okunuki, Yoko</creatorcontrib><creatorcontrib>Hasegawa, Eiichi</creatorcontrib><creatorcontrib>Klokman, Garrett</creatorcontrib><creatorcontrib>Kim, Clifford B</creatorcontrib><creatorcontrib>Krishnan, Anitha</creatorcontrib><creatorcontrib>Gregory-Ksander, Meredith</creatorcontrib><creatorcontrib>Husain, Deeba</creatorcontrib><creatorcontrib>Miller, Joan W</creatorcontrib><creatorcontrib>Connor, Kip M</creatorcontrib><title>Mouse model of ocular hypertension with retinal ganglion cell degeneration</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Ocular hypertension is a primary risk factor for glaucoma and results in retinal ganglion cell (RGC) degeneration. Current animal models of glaucoma lack severe RGC cell death as seen in glaucoma, making assessment of physiological mediators of cell death difficult. We developed a modified mouse model of ocular hypertension whereby long-lasting elevation of intraocular pressure (IOP) is achieved, resulting in significant reproducible damage to RGCs.
In this model, microbeads are mixed with hyaluronic acid and injected into the anterior chamber of C57BL/6J mice. The hyaluronic acid allows for a gradual release of microbeads, resulting in sustained blockage of Schlemm's canal. IOP elevation was bimodal during the course of the model's progression. The first peak occurred 1 hours after beads injection, with an IOP value of 44.69 ± 6.00 mmHg, and the second peak occurred 6-12 days post-induction, with an IOP value of 34.91 ± 5.21 mmHg. RGC damage was most severe in the peripheral retina, with a loss of 64.1% compared to that of untreated eyes, while the midperiphery exhibited a 32.4% loss, 4 weeks following disease induction.
These results suggest that sustained IOP elevation causes more RGC damage in the periphery than in the midperiphery of the retina. This model yields significant and reproducible RGC degeneration.</description><subject>Acids</subject><subject>Angiogenesis</subject><subject>Animal models</subject><subject>Animals</subject><subject>Anterior chamber</subject><subject>Automation</subject><subject>Beads</subject><subject>Biology and Life Sciences</subject><subject>Blockage</subject><subject>Cell cycle</subject><subject>Cell death</subject><subject>Complications and side effects</subject><subject>Damage</subject><subject>Degeneration</subject><subject>Disease Models, Animal</subject><subject>Eye (anatomy)</subject><subject>Field study</subject><subject>Glaucoma</subject><subject>Glaucoma - metabolism</subject><subject>Glaucoma - physiopathology</subject><subject>Hyaluronic acid</subject><subject>Hypertension</subject><subject>Immunohistochemistry</subject><subject>Intraocular pressure</subject><subject>Intraocular Pressure - physiology</subject><subject>Laboratory animals</subject><subject>Laboratory rats</subject><subject>Male</subject><subject>Medical schools</subject><subject>Medicine and Health Sciences</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Microspheres</subject><subject>Nanoparticles</subject><subject>Ocular Hypertension - metabolism</subject><subject>Ocular Hypertension - physiopathology</subject><subject>Ophthalmology</subject><subject>Physical Sciences</subject><subject>Retina</subject><subject>Retina - metabolism</subject><subject>Retina - physiopathology</subject><subject>Retinal Degeneration - metabolism</subject><subject>Retinal Degeneration - physiopathology</subject><subject>Retinal ganglion cells</subject><subject>Retinal Ganglion Cells - metabolism</subject><subject>Retinal Ganglion Cells - pathology</subject><subject>Risk analysis</subject><subject>Risk factors</subject><subject>Tomography, Optical Coherence</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNkktv1DAUhSMEoqXwDxBEQkKwmMGv2MkGqaqADiqqxGtrOc51xiNPPLUToP8ep5NWE9QFysLR9XfPtY9Plj3HaImpwO82fgidcsud72CJCCoFpg-yY1xRsuAE0YcH_0fZkxg3CBW05PxxdkQRZ6gi6Dj7_MUPEfKtb8Dl3uReD06FfH29g9BDF63v8t-2X-cBepvG5a3qWjdWNTiXN9BCB0H1qfI0e2SUi_BsWk-yHx8_fD87X1xcflqdnV4sNK9IvyhEQ7WipRGFULrGTckQxRXW2jQgqIAaEcG4QqICpnADjBiiScFrA0AYpyfZy73uzvkoJxuiJJgLhBkpykSs9kTj1Ubugt2qcC29svKm4EMrVeitdiCFqlkFUFaGK6YpVZQVZV0bxmpCeVEkrffTtKHeQqOh64NyM9H5TmfXsvW_JKcUYzIe5s0kEPzVALGXWxtH81QHyft0blFRxjDGCX31D3r_7SaqVekCtjM-zdWjqDwteFUwUTKaqOU9VPoa2FqdMmNsqs8a3s4aEtPDn75VQ4xy9e3r_7OXP-fs6wN2Dcr16-jdMEYmzkG2B3XwMQYwdyZjJMfI37ohx8jLKfKp7cXhA9013Wac_gWoivuf</recordid><startdate>20190114</startdate><enddate>20190114</enddate><creator>Mukai, Ryo</creator><creator>Park, Dong Ho</creator><creator>Okunuki, Yoko</creator><creator>Hasegawa, Eiichi</creator><creator>Klokman, Garrett</creator><creator>Kim, Clifford B</creator><creator>Krishnan, Anitha</creator><creator>Gregory-Ksander, Meredith</creator><creator>Husain, Deeba</creator><creator>Miller, Joan W</creator><creator>Connor, Kip M</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0003-1796-9232</orcidid><orcidid>https://orcid.org/0000-0002-2048-9080</orcidid></search><sort><creationdate>20190114</creationdate><title>Mouse model of ocular hypertension with retinal ganglion cell degeneration</title><author>Mukai, Ryo ; Park, Dong Ho ; Okunuki, Yoko ; Hasegawa, Eiichi ; Klokman, Garrett ; Kim, Clifford B ; Krishnan, Anitha ; Gregory-Ksander, Meredith ; Husain, Deeba ; Miller, Joan W ; Connor, Kip M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-57d3ca38f757acb1d8403191ccfde737eb02746a079e4a1de42f2c256bfee2463</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Acids</topic><topic>Angiogenesis</topic><topic>Animal models</topic><topic>Animals</topic><topic>Anterior chamber</topic><topic>Automation</topic><topic>Beads</topic><topic>Biology and Life Sciences</topic><topic>Blockage</topic><topic>Cell cycle</topic><topic>Cell death</topic><topic>Complications and side effects</topic><topic>Damage</topic><topic>Degeneration</topic><topic>Disease Models, Animal</topic><topic>Eye (anatomy)</topic><topic>Field study</topic><topic>Glaucoma</topic><topic>Glaucoma - metabolism</topic><topic>Glaucoma - physiopathology</topic><topic>Hyaluronic acid</topic><topic>Hypertension</topic><topic>Immunohistochemistry</topic><topic>Intraocular pressure</topic><topic>Intraocular Pressure - physiology</topic><topic>Laboratory animals</topic><topic>Laboratory rats</topic><topic>Male</topic><topic>Medical schools</topic><topic>Medicine and Health Sciences</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Microspheres</topic><topic>Nanoparticles</topic><topic>Ocular Hypertension - metabolism</topic><topic>Ocular Hypertension - physiopathology</topic><topic>Ophthalmology</topic><topic>Physical Sciences</topic><topic>Retina</topic><topic>Retina - metabolism</topic><topic>Retina - physiopathology</topic><topic>Retinal Degeneration - metabolism</topic><topic>Retinal Degeneration - physiopathology</topic><topic>Retinal ganglion cells</topic><topic>Retinal Ganglion Cells - metabolism</topic><topic>Retinal Ganglion Cells - pathology</topic><topic>Risk analysis</topic><topic>Risk factors</topic><topic>Tomography, Optical Coherence</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mukai, Ryo</creatorcontrib><creatorcontrib>Park, Dong Ho</creatorcontrib><creatorcontrib>Okunuki, Yoko</creatorcontrib><creatorcontrib>Hasegawa, Eiichi</creatorcontrib><creatorcontrib>Klokman, Garrett</creatorcontrib><creatorcontrib>Kim, Clifford B</creatorcontrib><creatorcontrib>Krishnan, Anitha</creatorcontrib><creatorcontrib>Gregory-Ksander, Meredith</creatorcontrib><creatorcontrib>Husain, Deeba</creatorcontrib><creatorcontrib>Miller, Joan W</creatorcontrib><creatorcontrib>Connor, Kip M</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mukai, Ryo</au><au>Park, Dong Ho</au><au>Okunuki, Yoko</au><au>Hasegawa, Eiichi</au><au>Klokman, Garrett</au><au>Kim, Clifford B</au><au>Krishnan, Anitha</au><au>Gregory-Ksander, Meredith</au><au>Husain, Deeba</au><au>Miller, Joan W</au><au>Connor, Kip M</au><au>Agudo-Barriuso, Marta</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mouse model of ocular hypertension with retinal ganglion cell degeneration</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2019-01-14</date><risdate>2019</risdate><volume>14</volume><issue>1</issue><spage>e0208713</spage><epage>e0208713</epage><pages>e0208713-e0208713</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Ocular hypertension is a primary risk factor for glaucoma and results in retinal ganglion cell (RGC) degeneration. Current animal models of glaucoma lack severe RGC cell death as seen in glaucoma, making assessment of physiological mediators of cell death difficult. We developed a modified mouse model of ocular hypertension whereby long-lasting elevation of intraocular pressure (IOP) is achieved, resulting in significant reproducible damage to RGCs.
In this model, microbeads are mixed with hyaluronic acid and injected into the anterior chamber of C57BL/6J mice. The hyaluronic acid allows for a gradual release of microbeads, resulting in sustained blockage of Schlemm's canal. IOP elevation was bimodal during the course of the model's progression. The first peak occurred 1 hours after beads injection, with an IOP value of 44.69 ± 6.00 mmHg, and the second peak occurred 6-12 days post-induction, with an IOP value of 34.91 ± 5.21 mmHg. RGC damage was most severe in the peripheral retina, with a loss of 64.1% compared to that of untreated eyes, while the midperiphery exhibited a 32.4% loss, 4 weeks following disease induction.
These results suggest that sustained IOP elevation causes more RGC damage in the periphery than in the midperiphery of the retina. This model yields significant and reproducible RGC degeneration.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>30640920</pmid><doi>10.1371/journal.pone.0208713</doi><tpages>e0208713</tpages><orcidid>https://orcid.org/0000-0003-1796-9232</orcidid><orcidid>https://orcid.org/0000-0002-2048-9080</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Acids Angiogenesis Animal models Animals Anterior chamber Automation Beads Biology and Life Sciences Blockage Cell cycle Cell death Complications and side effects Damage Degeneration Disease Models, Animal Eye (anatomy) Field study Glaucoma Glaucoma - metabolism Glaucoma - physiopathology Hyaluronic acid Hypertension Immunohistochemistry Intraocular pressure Intraocular Pressure - physiology Laboratory animals Laboratory rats Male Medical schools Medicine and Health Sciences Mice Mice, Inbred C57BL Microspheres Nanoparticles Ocular Hypertension - metabolism Ocular Hypertension - physiopathology Ophthalmology Physical Sciences Retina Retina - metabolism Retina - physiopathology Retinal Degeneration - metabolism Retinal Degeneration - physiopathology Retinal ganglion cells Retinal Ganglion Cells - metabolism Retinal Ganglion Cells - pathology Risk analysis Risk factors Tomography, Optical Coherence |
title | Mouse model of ocular hypertension with retinal ganglion cell degeneration |
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