Protein-unfolding Chaperones for the Treatment of Blindness

项目总结/摘要 该项目的目标是开发一种新的治疗应用，利用蛋白质解折叠ATP酶 用于治疗遗传性视网膜营养不良，包括色素性视网膜炎。这一战略的基础是 前提是，许多这些基因多样的遗传性疾病，其特点是缓慢的 然而，感光细胞神经元的即将死亡有一个共同的病因，即细胞毒性。 由于突变，蛋白质错误折叠。为了抵消这种毒性，我们在基因上引入了一种 蛋白质解折叠ATP酶从视网膜进入小鼠的视网膜杆光感受器用于净化目的 错误折叠的蛋白质为了验证我们的假设，并达到我们提出的研究目标，以下三个具体的 这项建议确定了目标。在具体目标1中，我们将研究 古细菌伴侣蛋白保护小鼠光感受器免受细胞毒性错误折叠蛋白的伤害。具体目标2 拟议的研究将确定这种干预的有效性，以避免视网膜病变的进展， 在两个建立的RP小鼠模型中的退化。具体目标3的重点是测试治疗 病毒载体的潜力，使蛋白质解折叠ATP酶进入光感受器细胞的交付。 这些研究将在小鼠中进行，将是开发类似治疗方法的第一步的一部分 在人类患者中针对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.