Chemical chaperones for Niemann-Pick C disease

尼曼-匹克 C 病的化学伴侣

• 批准号: 7124457
• 负责人: YIANNIS A IOANNOU
• 金额: $ 21.19万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7124457
• 关键词: Niemann Pick disease; bioassay; cell line; disease /disorder etiology; drug discovery /isolation; drug screening /evaluation; gene mutation; high throughput technology; membrane transport proteins; molecular chaperones; molecular pathology; pathologic process; phenotype; protein folding; protein localization; protein structure function; protein transport; vesicle /vacuole

DESCRIPTION (provided by applicant): NPC1 disease is a severe lysosomal lipidosis in which the egress of cholesterol and other lipids from the endosomal/ lysosomal (E/L) system is defective, leading to neurodegeneration and premature demise. The protein responsible for the major form of NPC disease, NPC1 is known. Preliminary characterization suggests that NPC1 may act as a lipid permease on the membranes of late endosomes. However, the exact function(s) of NPC1 and its role in NPC disease pathogenesis remain elusive and no form of treatment for this debilitating disorder is currently available. We hypothesize that many NPC1 mutations are disease causing due to the fact that the mutant proteins are unable to mature from the endoplasmic reticulum and are thus unable to be targeted to the late endosome. Pharmacologically relevant chemical chaperones have shown great promise recently in enhancing mutant protein maturation and thus partial rescue of protein activity. We will first establish an assay for detecting the maturation and ER exit of mutant NPC1 proteins. Second, we will use our in-house high throughput facility to identify chemical chaperones that can rescue mutant NPC1 proteins. These molecules will then be evaluated in cell-based assays to determine the level of NPC phenotype correction and assess their utility in future animal and NPC1 patient studies. Successful identification of small molecule chaperones will provide "Proof-of-principle" for this type of approach, and a new avenue of research for NPC1 and other devastating neurological disorders caused by membrane protein misfolding.

描述（由申请人提供）：NPC1疾病是一种严重的溶酶体脂质沉积症，其中胆固醇和其他脂质从内体/溶酶体（E/L）系统排出有缺陷，导致神经退行性变和过早死亡。NPC1是鼻咽癌疾病的主要形式。初步表征表明NPC1可能在晚期核内体的膜上起脂质渗透酶的作用。然而，NPC1的确切功能及其在NPC疾病发病机制中的作用仍然难以捉摸，目前还没有针对这种衰弱性疾病的治疗方法。我们假设许多NPC1突变是由于突变蛋白无法从内质网成熟从而无法靶向晚期内体而引起的疾病。近年来，药理学上相关的化学伴侣在促进突变蛋白成熟从而部分恢复蛋白质活性方面显示出很大的前景。我们将首先建立一种检测突变NPC1蛋白成熟和内质网出口的方法。其次，我们将使用我们内部的高通量设备来识别可以拯救突变的NPC1蛋白的化学伴侣。然后，这些分子将在基于细胞的分析中进行评估，以确定鼻咽癌表型纠正的水平，并评估它们在未来动物和NPC1患者研究中的效用。小分子伴侣的成功鉴定将为这种方法提供“原理证明”，并为研究NPC1和其他由膜蛋白错误折叠引起的毁灭性神经系统疾病提供新的途径。