Protein-unfolding Chaperones for the Treatment of Blindness

用于治疗失明的蛋白质展开伴侣

基本信息

批准号：
10408075
负责人：
MAXIM SOKOLOV
金额：
$ 36.86万
依托单位：
WEST VIRGINIA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10408075
关键词：
26S proteasome ATP phosphohydrolase Affect Alleles Archaea Blindness Breeding Cause of Death Cells Cessation of life Coupled Data Dependovirus Development Disease Effectiveness of Interventions Electroretinography Etiology Eye Failure Family Gene Mutation Genes Genetic Variation Goals Hereditary Disease Human Impairment Inflammation Inherited Intervention Knock-in Lead Mammals Metabolic stress Modeling Molecular Chaperones Monitor Mus Mutation Neurodegenerative Disorders Neurons Opsin Optical Coherence Tomography Organism Outcome Oxidative Stress Pathway interactions Patients Photoreceptors Procedures Prospective Studies Proteins Reporter Research Retinal Degeneration Retinal Diseases Retinal Dystrophy Retinal Photoreceptors Retinitis Pigmentosa Rhodopsin Rod System Techniques Temperature Testing Therapeutic Time Toxic effect Translating Viral Vector Visual Water base cytotoxic cytotoxicity disease-causing mutation efficacy evaluation improved in vitro Assay in vivo light microscopy microbial microorganism misfolded protein mouse model multicatalytic endopeptidase complex non-Native novel therapeutic intervention novel therapeutics protective effect protein aggregation protein degradation protein function protein misfolding proteostasis purge retinal rods therapeutic evaluation unfoldase

项目摘要

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.

项目摘要/摘要该项目的目的是开发一种利用蛋白质展开ATPase的新型治疗应用用于治疗遗传性视网膜营养不良，包括色素性视网膜炎。该策略基于前提是许多这些遗传多样的遗传性疾病的特征是慢尽管如此突变导致蛋白质错误折叠。为了抵消这种毒性，我们遗传引入了从古细菌进入小鼠的视网膜杆感光体的蛋白质无折叠ATPase目的错误折叠的蛋白质。为了检验我们的假设并实现我们提出的研究目标，以下三个特定的该提案已确定目标。在特定目的1中，我们将研究该机制古细菌伴侣可保护小鼠感光体免受细胞毒性错误折叠蛋白的影响。特定目标2 拟议的研究将确定这种干预措施避免视网膜的进展的有效性两种已建立的RP小鼠模型的变性。特定目标3的重点是测试治疗性病毒载体的电势能够递送蛋白质的ATPase进入光感受器细胞。这些研究将在小鼠中进行，将是开发类似治疗的第一步的一部分针对色素性视网膜炎在人类患者中的应用。