Suppressing thyroid hormone signaling to protect cones in retinal degeneration

描述(申请人提供)：遗传性视网膜退行性疾病，如视网膜色素变性和视锥视杆细胞营养不良，影响全世界大约3000人中的1人。老年性黄斑变性是老年人失明的主要原因。尽管致病基因和发病机制存在显著的异质性，但最终导致视力障碍和失明的是视锥细胞感光细胞的渐进性死亡。目前还没有治疗视网膜变性的方法。甲状腺激素(TH)信号调节细胞的增殖、分化和凋亡。在视网膜中，TH信号在视锥蛋白的表达和模式形成中起着核心作用。利用几种视网膜变性小鼠模型，我们的初步研究表明，TH信号影响视锥细胞的存活。抑制TH信号(通过抗甲状腺治疗)保留锥体，刺激TH信号(通过甲状腺激素T3治疗)恶化锥体。局部组织中的TH信号主要通过TH受体(Thr)和使T3，3型碘甲状腺原氨酸脱碘酶(DIO3)失活的酶来调节。这项研究的目的是确定在视网膜局部抑制TH信号是否保留了视锥细胞。我们提出了两个具体目标来解决这个问题。第一个目的是确定阻断视网膜中的苏氨酸是否能保留视网膜变性模型小鼠的视锥细胞。RPE65-/-是Leber先天性黑色症的模型，cpfl1是色盲的模型，小鼠将通过眼部注射Thr拮抗剂进行治疗，并在给药后评估视锥细胞的存活率。还将评估缺乏Thr�(视锥表达�类型的Thr，RPE65-/-/Thr�-/-和CPFl1/Thr�-/-)的RPE65-/-和CPFl1/Thr�-/-小鼠的视锥存活率，以确定当缺少Thr�时，视锥是否被保存。第二个目的是确定增强视网膜中Dio3的表达/功能是否保留了视锥细胞。我们将通过腺相关病毒(AAV)介导的转基因传递，在RPE65-/-和cpfl1小鼠的视网膜中过表达dio3。视锥存活将在转基因后进行评估。这项拟议研究的完成将确定在视网膜局部抑制TH信号是否保留了视网膜变性中的视锥细胞。具体地说，它将确定在视网膜中阻断Thr和过度表达/激活Dio3是否保护视锥细胞。我们期待的结果将导致一种新的、本质上不同的视网膜变性管理方法。

DESCRIPTION (provided by applicant): Inherited retinal degenerative diseases such as retinitis pigmentosa and cone-rod dystrophies affect approximately one in 3,000 individuals worldwide. Age-related macular degeneration is the leading cause of blindness among the elderly. Despite a remarkable heterogeneity of disease-causing genes and pathogenesis, it is the progressive death of cone photoreceptors that ultimately leads to vision impairment and blindness. There is currently no treatment available for retinal degeneration. Thyroid hormone (TH) signaling regulates cell proliferation, differentiation, and apoptosis. In the retina, TH signaling plays a central role in cone opsin expression and patterning. Using several retinal degeneration mouse models, our preliminary studies showed that TH signaling affects cone viability. Suppressing TH signaling (by anti-thyroid treatment) preserves cones and stimulating TH signaling (by thyroid hormone T3 treatment) deteriorates cones. TH signaling in local tissue is primarily regulated via TH receptor (ThR) and the enzyme that inactivates T3, type 3 iodothyronine deiodinase (DIO3). The objective of this study is to determine if suppressing TH signaling locally in the retina preserves cones. We propose two specific aims to address the question. The first aim is to determine whether blocking ThR in the retina preserves cones in retinal degeneration model mice. Rpe65-/-, a model of Leber congenital amaurosis, and cpfl1, a model of achromatopsia, mice will be treated with ThR antagonists via ocular delivery, and cone survival will be evaluated following drug administration. Cone survival will also be evaluated in Rpe65-/- and cpfl1 mice lacking ThR� (cones express � type of ThR, Rpe65-/-/Thr�-/- and cpfl1/Thr�-/-) to determine whether cones are preserved when ThR� is absent. The second aim is to determine whether enhancing expression/function of DIO3 in the retina preserves cones. We will overexpress DIO3 in the retinas of Rpe65-/- and cpfl1 mice through adeno-associated viral (AAV) mediated transgene delivery. Cone survival will be evaluated following transgene delivery. Completion of the proposed study will determine whether suppressing TH signaling locally in the retina preserves cones in retinal degeneration. Specifically, it will establish wheter blocking ThR and overexpressing/activating DIO3 in the retina protects cones. We anticipate an outcome that will lead to a novel and substantially different approach for retinal degeneration management.