Role of impaired protein degradation in photoreceptor degeneration

描述（由申请人提供）：本研究计划的长期目标是了解视网膜变性的分子和细胞机制，并寻求缓解或减缓疾病进展的潜在治疗方法。在本申请中，我们建议探索这样的假设，即视网膜色素变性和相关疾病中导致感光细胞死亡的主要应激因素是蛋白酶体降解大量错误折叠或错误定位的蛋白质的能力不足，这些蛋白质是潜在病理学的结果。我们的初步数据表明，蛋白酶体功能不全是在四种不同的小鼠模型中观察到的光感受器变性的早期阶段，在某些情况下，这种损害变得突出的最早的形态异常之前，可以确定。目的1将致力于一个详细的机制表征蛋白酶体不足的退化杆两个互补的动物模型，转导蛋白 γ亚基敲除和P23 H小鼠。最重要的是，我们将解决受影响的光感受器是否遭受蛋白酶体过载，即其蛋白酶体处理异常高负荷的错误折叠蛋白的能力不足，或者潜在的病理学通过抑制其活性或改变其亚基组成直接影响蛋白酶体。目标2将探讨 不同形式视网膜变性中蛋白酶体功能不全的患病率。我们将测试它是否可以检测到杆遭受异常信号的光转导级联反应，并阐明它是否发生在小鼠患有突变，影响锥比杆更显着。目的3：探讨蛋白酶体是否可以作为治疗视网膜变性疾病的靶点。我们将探讨是否可以通过基因治疗或旨在增加受影响的光感受器中蛋白酶体活性的药物治疗来减缓或预防病理学的发作。

DESCRIPTION (provided by applicant): 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 γ-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 retinal degenerative diseases. 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.