Role of impaired protein degradation in photoreceptor degeneration

项目总结 这项研究计划的长期目标是了解分子和细胞 视网膜变性的机制和寻找潜在的治疗方法 减缓或减缓疾病进展的。在本应用程序中，我们建议探索 视网膜炎光感受器细胞死亡的主要应激因素假说 色素变性及相关疾病是蛋白酶体降解大量的能力不足 由于潜在的病理而出现的错误折叠或错误定位的蛋白质。我们的 初步数据表明，蛋白酶体功能不全在早期观察到。 四种不同小鼠模型的光感受器退化，在某些情况下，这种损害 在最早的形态异常被识别之前就变得突出了。目标1 将致力于蛋白酶体功能不全的详细机制描述。 两种互补动物模型的退化杆，转导蛋白？亚单位敲除和 P23H小鼠。最重要的是，我们将解决受影响的光感受器是否会受到 蛋白酶体超载，即其蛋白酶体处理异常高的能力不足 大量错误折叠的蛋白质，或者潜在的病理通过直接影响蛋白酶体 抑制它们的活性或改变它们的亚基组成。目标2将探讨 蛋白酶体功能不全跨越不同形式的视网膜变性。我们将测试它是否 可以在光转导级联中遭受异常信号的杆状细胞中检测到 并阐明它是否发生在遭受突变的小鼠身上，这些突变对锥体的影响更大 比棒子要大得多。AIM 3将评估蛋白酶体是否可以作为一种治疗方法 治疗视网膜退行性疾病的靶点。我们将探讨是否会出现 病理可以通过基因治疗或药物治疗来延缓或预防 以增加受影响的光感受器中的蛋白酶体活性。

PROJECT SUMMARY The long-term goal of this research program is to understand the molecular and cellular mechanisms underlying retinal degeneration and to seek potential therapeutic approaches alleviating or slowing disease progression. In this application, we propose to explore the hypothesis that a major stress factor contributing to photoreceptor cell death in retinitis pigmentosa and related diseases is insufficient ability of proteasomes to degrade large amounts of misfolded or mistargeted proteins that appear as a result of the underlying pathology. Our preliminary data indicate that proteasomal insufficiency is observed at early stages of photoreceptor degeneration in four different mouse models and, in some cases, this impairment becomes prominent before the earliest morphological abnormalities could be identified. Aim 1 will be devoted to a detailed mechanistic characterization of proteasomal insufficiency in degenerating rods of two complementary animal models, transducin ¿-subunit knockout and P23H mouse. Most importantly, we will address whether affected photoreceptors suffer from proteasomal overload, i.e. insufficient capacity of their proteasomes to process abnormally high loads of misfolded proteins, or the underlying pathology affects proteasomes directly by inhibiting their activity or altering their subunit composition. Aim 2 will explore the prevalence of proteasomal insufficiency across different forms of retinal degeneration. We will test whether it could be detected in rods suffering from aberrant signaling in the phototransduction cascade and elucidate whether it takes place in mice suffering from mutations which affect cones more significantly than rods. Aim 3 will evaluate whether proteasomes could serve as a therapeutic target in treating degenerative diseases of the retina. We will explore whether the onset of pathology can be slowed or prevented by gene therapy or pharmacological treatments designed to increase proteasomal activity in affected photoreceptors.