Chronic Dicer1 deficiency promotes atrophic and neovascular outer retinal pathologies in mice.
Dicer
choroidal neovascularization
inflammasome
retina
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
04 02 2020
04 02 2020
Historique:
pubmed:
23
1
2020
medline:
17
6
2020
entrez:
23
1
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31964819
pii: 1909761117
doi: 10.1073/pnas.1909761117
pmc: PMC7007521
doi:
Substances chimiques
Dicer1 protein, mouse
EC 3.1.26.3
Ribonuclease III
EC 3.1.26.3
DEAD-box RNA Helicases
EC 3.6.4.13
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2579-2587Subventions
Organisme : NEI NIH HHS
ID : R01 EY017950
Pays : United States
Organisme : NEI NIH HHS
ID : R01 EY029799
Pays : United States
Organisme : NEI NIH HHS
ID : R01 EY017182
Pays : United States
Organisme : NEI NIH HHS
ID : R01 EY024068
Pays : United States
Organisme : NIGMS NIH HHS
ID : DP1 GM114862
Pays : United States
Organisme : NEI NIH HHS
ID : R01 EY028027
Pays : United States
Organisme : NHLBI NIH HHS
ID : T32 HL007284
Pays : United States
Organisme : NCATS NIH HHS
ID : KL2 TR001996
Pays : United States
Organisme : NEI NIH HHS
ID : R01 EY022238
Pays : United States
Organisme : NEI NIH HHS
ID : K99 EY024336
Pays : United States
Organisme : NEI NIH HHS
ID : R01 EY019943
Pays : United States
Organisme : NEI NIH HHS
ID : R00 EY024336
Pays : United States
Informations de copyright
Copyright © 2020 the Author(s). Published by PNAS.
Déclaration de conflit d'intérêts
Competing interest statement: J.A. is a co-founder of iVeena Holdings, iVeena Delivery Systems, and Inflammasome Therapeutics, and has been a consultant for Allergan, Biogen, Boehringer-Ingelheim, Immunovant, Janssen, Olix Pharmaceuticals, Retinal Solutions, and Saksin LifeSciences unrelated to this work. B.K.A. is a co-founder of iVeena Holdings, iVeena Delivery Systems, and Inflammasome Therapeutics, and has been a consultant to Alcon, Genentech, and Johnson & Johnson unrelated to this work. H.U., S.F., B.J.F., N.K., B.K.A., J.A., and B.D.G. are named as inventors on patent applications related to the intellectual property described in this manuscript that have been filed by the University of Virginia, the University of Kentucky, or the University of Utah.
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