Suppressing thyroid hormone signaling to protect cones in retinal degeneration

描述（由申请人提供）：遗传性视网膜变性疾病，如视网膜色素变性和视锥-视杆细胞营养不良，影响全球约3,000人中的一人。视网膜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具有显著的异质性，但最终导致视力障碍和失明的是视锥细胞的进行性死亡。目前还没有治疗视网膜变性的方法。甲状腺激素（TH）信号传导调节细胞增殖、分化和凋亡。在视网膜中，TH信号传导在视锥细胞视蛋白表达和图案形成中起核心作用。使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活力。抑制TH信号传导（通过抗甲状腺治疗）保留视锥细胞，刺激TH信号传导（通过甲状腺激素T3治疗）使视锥细胞恶化。局部组织中的TH信号传导主要通过TH受体（ThR）和使T3失活的酶，3型碘甲腺原氨酸脱碘酶（DIO 3）来调节。本研究的目的是确定是否抑制TH信号在视网膜局部保存锥。我们提出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ThR是否保留视网膜变性模型小鼠中的视锥细胞。Rpe 65-/-（Leber先天性黑蒙模型）和cpfl 1（全色盲模型）小鼠将通过眼部递送用ThR拮抗剂处理，并在药物施用后评价视锥细胞存活。还将在缺乏ThR β的Rpe 65-/-和cpfl 1小鼠中评估视锥细胞存活率（视锥细胞表达ThR β型，Rpe 65-/-/Thr β-/-和cpfl 1/Thr β-/-），以确定当ThR β缺失时视锥细胞是否被保留。第二个目的是确定增强DIO 3在视网膜中的表达/功能是否保留视锥细胞。我们将通过腺相关病毒（AAV）介导的转基因递送在Rpe 65-/-和cpfl 1小鼠的视网膜中过表达DIO 3。在转基因递送后评价球果存活。完成拟议的研究将确定是否抑制TH信号在视网膜局部保留锥视网膜变性。具体而言，它将确定视网膜中阻断ThR和过表达/激活DIO 3是否保护视锥细胞。我们预计，这将导致一个新的和实质上不同的方法视网膜变性管理的结果。

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.