Protein-unfolding Chaperones for the Treatment of Blindness

项目摘要/摘要 这个项目的目标是开发一种新的治疗应用，它利用一种蛋白质展开的ATPase 用于治疗遗传性视网膜营养不良，包括视网膜色素变性。这一策略基于 前提是许多这些遗传多样性的遗传性疾病，其特点是慢性病 然而，光感受器神经元即将死亡的共同原因是 蛋白质因突变而错误折叠。为了抵消这种毒性，我们在基因上引入了一种 古生代ATPase蛋白解离于小鼠视网膜视杆感光细胞的净化作用 错误折叠的蛋白质。为了验证我们的假设并实现我们提出的研究目标，以下三个具体的 在这项提案中已经确定了目标。在具体目标1中，我们将研究 古生菌伴侣保护小鼠的光感受器免受细胞毒性错误折叠蛋白的影响。的具体目标2 拟议的研究将确定这种干预措施对避免视网膜进展的有效性 两种已建立的RP小鼠模型的退行性变。具体目标3的重点是测试治疗方法 一种病毒载体的潜力，能够将解开的ATPase蛋白运送到光感受器细胞中。 这些将在老鼠身上进行的研究将是开发类似疗法的第一步的一部分。 人类患者视网膜色素变性的应用。

PROJECT SUMMARY/ABSTRACT The goal of this project is to develop a novel therapeutic application that utilizes a protein unfolding ATPase for the treatment of inherited retinal dystrophies, including retinitis pigmentosa. This strategy is based on the premise that many of these genetically diverse hereditary diseases, which are characterized by the slow impending death of photoreceptor neurons, nevertheless, share a common etiology from the cytotoxicity of proteins misfolded as a result of mutations. To counteract this toxicity, we have genetically introduced a protein-unfolding ATPase from Archaea into the retinal rod photoreceptors of mice for the purpose of purging misfolded proteins. To test our hypothesis and attain our proposed research goals, the following three Specific Aims have been identified in this proposal. In Specific Aim 1 we will investigate the mechanism whereby the archaeal chaperone protects mouse photoreceptors from cytotoxic misfolded proteins. Specific Aim 2 of the proposed studies will ascertain the effectiveness of this intervention to avert the progression of retinal degeneration in two established RP mouse models. The focus of Specific Aim 3 is testing the therapeutic potential of a viral vector that enables the delivery of the protein unfolding ATPase into photoreceptor cells. These studies, to be conducted in mice, will be part of the first step toward developing a similar therapeutic application against retinitis pigmentosa in human patients.