Targeting miR-181a/b in retinitis pigmentosa: implications for disease progression and therapy.

Autor: Costa BLD; Jonas Children's Vision Care (JCVC) and Barbara & Donald Jonas Stem Cell Laboratory, New York-Presbyterian Hospital, New York, NY, USA.; Department of Biomedical Engineering, Columbia University, New York, NY, USA., Quinn PMJ; Department of Ophthalmology, Columbia University Irving Medical Center, New York, NY, USA., Wu WH; Jonas Children's Vision Care (JCVC) and Barbara & Donald Jonas Stem Cell Laboratory, New York-Presbyterian Hospital, New York, NY, USA.; Department of Ophthalmology, Columbia University Irving Medical Center, New York, NY, USA., Liu S; Jonas Children's Vision Care (JCVC) and Barbara & Donald Jonas Stem Cell Laboratory, New York-Presbyterian Hospital, New York, NY, USA.; Department of Biomedical Engineering, Columbia University, New York, NY, USA., Nolan ND; Jonas Children's Vision Care (JCVC) and Barbara & Donald Jonas Stem Cell Laboratory, New York-Presbyterian Hospital, New York, NY, USA.; Department of Biomedical Engineering, Columbia University, New York, NY, USA., Demirkol A; Jonas Children's Vision Care (JCVC) and Barbara & Donald Jonas Stem Cell Laboratory, New York-Presbyterian Hospital, New York, NY, USA.; Department of Ophthalmology, Columbia University Irving Medical Center, New York, NY, USA., Tsai YT; Jonas Children's Vision Care (JCVC) and Barbara & Donald Jonas Stem Cell Laboratory, New York-Presbyterian Hospital, New York, NY, USA.; Department of Biomedical Engineering, Columbia University, New York, NY, USA., Caruso SM; Jonas Children's Vision Care (JCVC) and Barbara & Donald Jonas Stem Cell Laboratory, New York-Presbyterian Hospital, New York, NY, USA.; Department of Biomedical Engineering, Columbia University, New York, NY, USA., Cabral T; Department of Specialized Medicine, CCS and Vision Center Unit, Ophthalmology EBSERH, HUCAM/CCS, UFES-Federal University of Espírito Santo (UFES), Vitória, Brazil.; Department of Ophthalmology, Federal University of Sao Paulo (UNIFESP), São Paulo, Brazil., Wang NK; Jonas Children's Vision Care (JCVC) and Barbara & Donald Jonas Stem Cell Laboratory, New York-Presbyterian Hospital, New York, NY, USA.; Department of Ophthalmology, Columbia University Irving Medical Center, New York, NY, USA., Tsang SH; Jonas Children's Vision Care (JCVC) and Barbara & Donald Jonas Stem Cell Laboratory, New York-Presbyterian Hospital, New York, NY, USA. sht2@columbia.edu.; Department of Biomedical Engineering, Columbia University, New York, NY, USA. sht2@columbia.edu.; Department of Ophthalmology, Columbia University Irving Medical Center, New York, NY, USA. sht2@columbia.edu.; Department of Pathology & Cell Biology, Columbia University Irving Medical Center, New York, NY, USA. sht2@columbia.edu.; Columbia Stem Cell Initiative, Institute of Human Nutrition ,Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA. sht2@columbia.edu.; Columbia University Irving Medical Center, Hammer Health Sciences Center 205b, 701 West 168th Street, New York, NY, 10032, USA. sht2@columbia.edu.
Jazyk: angličtina
Zdroj: Cell & bioscience [Cell Biosci] 2024 May 21; Vol. 14 (1), pp. 64. Date of Electronic Publication: 2024 May 21.
DOI: 10.1186/s13578-024-01243-3
Abstrakt: Background: Retinitis pigmentosa (RP) is a genetically heterogeneous group of degenerative disorders causing progressive vision loss due to photoreceptor death. RP affects other retinal cells, including the retinal pigment epithelium (RPE). MicroRNAs (miRs) are implicated in RP pathogenesis, and downregulating miR-181a/b has shown therapeutic benefit in RP mouse models by improving mitochondrial function. This study investigates the expression profile of miR-181a/b in RPE cells and the neural retina during RP disease progression. We also evaluate how miR-181a/b downregulation, by knocking out miR-181a/b-1 cluster in RPE cells, confers therapeutic efficacy in an RP mouse model and explore the mechanisms underlying this process.
Results: Our findings reveal distinct expression profiles, with downregulated miR-181a/b in RPE cells suggesting a protective response and upregulated miR-181a/b in the neural retina indicating a role in disease progression. We found that miR-181a/b-2, encoded in a separate genomic cluster, compensates for miR-181a/b-1 ablation in RPE cells at late time points. The transient downregulation of miR-181a/b in RPE cells at post-natal week 6 (PW6) led to improved RPE morphology, retarded photoreceptor degeneration and decreased RPE aerobic glycolysis.
Conclusions: Our study elucidates the underlying mechanisms associated with the therapeutic modulation of miR-181a/b, providing insights into the metabolic processes linked to its RPE-specific downregulation. Our data further highlights the impact of compensatory regulation between miR clusters with implications for the development of miR-based therapeutics.
(© 2024. The Author(s).)
Databáze: MEDLINE
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