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Hongwei Ma, Fan Yang, Josh Belcher, Michael Butler, T. Michael Redmond, Thomas S Scanlan, Sanford L. Boye, William W Hauswirth, Xi-Qin Ding; Ocular Inhibition of Thyroid Hormone Signaling Protects Cone Photoreceptors in Mouse Models of Retinal Degeneration. Invest. Ophthalmol. Vis. Sci. 201657(12):.
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© ARVO (1962-2015); The Authors (2016-present)
Thyroid hormone (TH) signaling regulates cell proliferation, differentiation, metabolism, and apoptosis. In the retina, TH signaling plays a central role in cone opsin expression and patterning. We previously showed that suppressing TH signaling by anti-thyroid treatment preserves cones in mouse models of retinal degeneration. This work investigates the effectiveness of inhibition of TH signaling locally in the retina for cone protection.
We used two strategies to suppress TH signaling in the mouse retina: 1) blocking thyroid hormone receptor (TR) using TR antagonists NH3 and 1-850, and 2) reducing cellular level of 3,5,3’-triiodothyronine (T3) by overexpression of T3-degrading enzyme type 3 iodothyronine deiodinase (DIO3). Postnatal day 5 (P5) Rpe65-/- and Rpe65-/-/Nrl-/- mice received NH3 or 1-850 by intravitreal injection or by eyedrops (containing 0.3% NH3, three time a day), or were subretinally injected with viral vectors that harbor a transgene directing the expression of human DIO3 (AAV5-IRBP/Gnat2-hDIO3) specifically in cones. Mice were analyzed for cone death by terminal deoxynucleotidyltransferase dUTP nick end-labeling (TUNEL) at P15 and for cone density by immunofluorescence labeling of cone markers at P25.
We found that inhibition of TR and overexpression of DIO3 significantly improved cone survival and function. Intravitreal delivery of NH3 increased cone density by about 30% and reduced TUNEL-positive cells by about 30%, compared with those in vehicle-treated controls. Similar results were observed in mice treated with 1-850. Topical administration of NH3 reduced TUNEL-positive cells by about 37% in Rpe65-/-/Nrl-/- mice. Cone density in Rpe65-/- mice treated with AAV5-IRBP/Gnat2-hDIO3 increased by about 45%, compared with vehicle-treated controls.
This work shows that local suppression of TH signaling by TR inhibition or overexpression of DIO3 improves cone survival in mouse models of retinal degeneration. Our findings suggest that suppressing TH signaling locally in the retina represents a strategy for protection of cones in retinal degeneration.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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