Role of impaired protein degradation in photoreceptor degeneration

蛋白质降解受损在光感受器变性中的作用

基本信息

批准号：
8705524
负责人：
Vadim Y Arshavsky
金额：
$ 44.39万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8705524
关键词：
Address Affect Animal Model Animals Biological Factors Blindness Cell Death Cellular Stress Chemicals Chemopreventive Agent Cone Data Defect Degenerative Disorder Disease Disease Progression Disease model Employee Strikes Foundations Future Gene Delivery Genes Goals Health Human Hybrids Impairment Individual Infection Inherited Intervention Knock-out Modeling Molecular Monitor Mus Mutant Strains Mice Mutation Nature Neuroprotective Agents Pathology Patients Pharmacologic Substance Pharmacological Treatment Photoreceptors Phototransduction Prevalence Process Proteins Proteolysis RPE65 protein Recombinants Reporter Research Retina Retinal Degeneration Retinal Diseases Retinitis Pigmentosa Rhodopsin Role Signal Transduction Staging Stress Sulforaphane System Testing Therapeutic Therapeutic Intervention Transducin Ubiquitin Up-Regulation Vision Vision Disorders base cell type combat cruciferous vegetable design effective therapy gene therapy in vivo insight mouse model multicatalytic endopeptidase complex photoreceptor degeneration pre-clinical prevent programs protein degradation protein misfolding public health relevance research study response retinal rods stressor therapeutic target therapy design

项目摘要

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 ?-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.

描述（由申请人提供）：该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，并寻求减轻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：导致色素性视网膜炎和相关疾病中感光细胞死亡的主要应激因素是蛋白酶体降解大量因潜在病理而出现的错误折叠或错误定位的蛋白质的能力不足。我们的初步数据表明，在四种不同的小鼠模型中，在光感受器变性的早期阶段观察到蛋白酶体不足，并且在某些情况下，这种损伤在最早的形态异常被识别之前变得突出。目标 1 将致力于两种互补动物模型（转导蛋白 β 亚基敲除和 P23H 小鼠）退化视杆细胞中蛋白酶体功能不全的详细机制表征。最重要的是，我们将解决受影响的光感受器是否患有蛋白酶体超载，即其蛋白酶体处理异常高负载的错误折叠蛋白质的能力不足，或者潜在的病理学通过抑制其活性或改变其亚基组成来直接影响蛋白酶体。目标 2 将探索不同形式的视网膜变性中蛋白酶体功能不全的患病率。我们将测试是否可以在光转导级联中遭受异常信号传导的视杆细胞中检测到它，并阐明它是否发生在遭受突变的小鼠中，这些突变对视锥细胞的影响比对视杆细胞的影响更显着。目标 3 将评估蛋白酶体是否可以作为治疗视网膜退行性疾病的治疗靶点。我们将探讨是否可以通过基因疗法或旨在增加受影响光感受器中蛋白酶体活性的药物治疗来减缓或预防病理的发生。