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Chronic Dicer1 deficiency promotes atrophic and neovascular outer retinal pathologies in mice
Degeneration of the retinal pigmented epithelium (RPE) and aberrant blood vessel growth in the eye are advanced-stage processes in blinding diseases such as age-related macular degeneration (AMD), which affect hundreds of millions of people worldwide. Loss of the RNase DICER1, an essential factor in...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7007521/ https://www.ncbi.nlm.nih.gov/pubmed/31964819 http://dx.doi.org/10.1073/pnas.1909761117 |
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author | Wright, Charles B. Uehara, Hironori Kim, Younghee Yasuma, Tetsuhiro Yasuma, Reo Hirahara, Shuichiro Makin, Ryan D. Apicella, Ivana Pereira, Felipe Nagasaka, Yosuke Narendran, Siddharth Fukuda, Shinichi Albuquerque, Romulo Fowler, Benjamin J. Bastos-Carvalho, Ana Georgel, Philippe Hatada, Izuho Chang, Bo Kerur, Nagaraj Ambati, Balamurali K. Ambati, Jayakrishna Gelfand, Bradley D. |
author_facet | Wright, Charles B. Uehara, Hironori Kim, Younghee Yasuma, Tetsuhiro Yasuma, Reo Hirahara, Shuichiro Makin, Ryan D. Apicella, Ivana Pereira, Felipe Nagasaka, Yosuke Narendran, Siddharth Fukuda, Shinichi Albuquerque, Romulo Fowler, Benjamin J. Bastos-Carvalho, Ana Georgel, Philippe Hatada, Izuho Chang, Bo Kerur, Nagaraj Ambati, Balamurali K. Ambati, Jayakrishna Gelfand, Bradley D. |
author_sort | Wright, Charles B. |
collection | PubMed |
description | Degeneration of the retinal pigmented epithelium (RPE) and aberrant blood vessel growth in the eye are advanced-stage processes in blinding diseases such as age-related macular degeneration (AMD), which affect hundreds of millions of people worldwide. Loss of the RNase DICER1, an essential factor in micro-RNA biogenesis, is implicated in RPE atrophy. However, the functional implications of DICER1 loss in choroidal and retinal neovascularization are unknown. Here, we report that two independent hypomorphic mouse strains, as well as a separate model of postnatal RPE-specific DICER1 ablation, all presented with spontaneous RPE degeneration and choroidal and retinal neovascularization. DICER1 hypomorphic mice lacking critical inflammasome components or the innate immune adaptor MyD88 developed less severe RPE atrophy and pathological neovascularization. DICER1 abundance was also reduced in retinas of the JR5558 mouse model of spontaneous choroidal neovascularization. Finally, adenoassociated vector-mediated gene delivery of a truncated DICER1 variant (OptiDicer) reduced spontaneous choroidal neovascularization in JR5558 mice. Collectively, these findings significantly expand the repertoire of DICER1 in preserving retinal homeostasis by preventing both RPE degeneration and pathological neovascularization. |
format | Online Article Text |
id | pubmed-7007521 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-70075212020-02-18 Chronic Dicer1 deficiency promotes atrophic and neovascular outer retinal pathologies in mice Wright, Charles B. Uehara, Hironori Kim, Younghee Yasuma, Tetsuhiro Yasuma, Reo Hirahara, Shuichiro Makin, Ryan D. Apicella, Ivana Pereira, Felipe Nagasaka, Yosuke Narendran, Siddharth Fukuda, Shinichi Albuquerque, Romulo Fowler, Benjamin J. Bastos-Carvalho, Ana Georgel, Philippe Hatada, Izuho Chang, Bo Kerur, Nagaraj Ambati, Balamurali K. Ambati, Jayakrishna Gelfand, Bradley D. Proc Natl Acad Sci U S A Biological Sciences Degeneration of the retinal pigmented epithelium (RPE) and aberrant blood vessel growth in the eye are advanced-stage processes in blinding diseases such as age-related macular degeneration (AMD), which affect hundreds of millions of people worldwide. Loss of the RNase DICER1, an essential factor in micro-RNA biogenesis, is implicated in RPE atrophy. However, the functional implications of DICER1 loss in choroidal and retinal neovascularization are unknown. Here, we report that two independent hypomorphic mouse strains, as well as a separate model of postnatal RPE-specific DICER1 ablation, all presented with spontaneous RPE degeneration and choroidal and retinal neovascularization. DICER1 hypomorphic mice lacking critical inflammasome components or the innate immune adaptor MyD88 developed less severe RPE atrophy and pathological neovascularization. DICER1 abundance was also reduced in retinas of the JR5558 mouse model of spontaneous choroidal neovascularization. Finally, adenoassociated vector-mediated gene delivery of a truncated DICER1 variant (OptiDicer) reduced spontaneous choroidal neovascularization in JR5558 mice. Collectively, these findings significantly expand the repertoire of DICER1 in preserving retinal homeostasis by preventing both RPE degeneration and pathological neovascularization. National Academy of Sciences 2020-02-04 2020-01-21 /pmc/articles/PMC7007521/ /pubmed/31964819 http://dx.doi.org/10.1073/pnas.1909761117 Text en Copyright © 2020 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/ https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) . |
spellingShingle | Biological Sciences Wright, Charles B. Uehara, Hironori Kim, Younghee Yasuma, Tetsuhiro Yasuma, Reo Hirahara, Shuichiro Makin, Ryan D. Apicella, Ivana Pereira, Felipe Nagasaka, Yosuke Narendran, Siddharth Fukuda, Shinichi Albuquerque, Romulo Fowler, Benjamin J. Bastos-Carvalho, Ana Georgel, Philippe Hatada, Izuho Chang, Bo Kerur, Nagaraj Ambati, Balamurali K. Ambati, Jayakrishna Gelfand, Bradley D. Chronic Dicer1 deficiency promotes atrophic and neovascular outer retinal pathologies in mice |
title | Chronic Dicer1 deficiency promotes atrophic and neovascular outer retinal pathologies in mice |
title_full | Chronic Dicer1 deficiency promotes atrophic and neovascular outer retinal pathologies in mice |
title_fullStr | Chronic Dicer1 deficiency promotes atrophic and neovascular outer retinal pathologies in mice |
title_full_unstemmed | Chronic Dicer1 deficiency promotes atrophic and neovascular outer retinal pathologies in mice |
title_short | Chronic Dicer1 deficiency promotes atrophic and neovascular outer retinal pathologies in mice |
title_sort | chronic dicer1 deficiency promotes atrophic and neovascular outer retinal pathologies in mice |
topic | Biological Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7007521/ https://www.ncbi.nlm.nih.gov/pubmed/31964819 http://dx.doi.org/10.1073/pnas.1909761117 |
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