HTS of NPC1 promoter activators

NPC1 启动子激活剂的 HTS

• 批准号: 8067160
• 负责人: YIANNIS A IOANNOU
• 金额: $ 4.2万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8067160
• 关键词: Affect; Alleles; Biological Assay; Brain; Cell Culture Techniques; Cell Line; Chemicals; Collection; Disease; Future; Genes; Hereditary Disease; Lipids; Lipoidosis; Missense Mutation; Modality; Modeling; Molecular Bank; Mutation; Nerve Degeneration; Neuraxis; Neurologic; Pharmaceutical Preparations; Phenotype; Production; Proteins; Screening procedure; Specificity; Supraoptic Vertical Ophthalmoplegia; System; Testing; Therapeutic; Up-Regulation; candidate identification; counterscreen; disease phenotype; drug development; high throughput screening; in vitro Assay; in vivo; lipid transport; mouse model; mutant; novel strategies; promoter; small molecule; therapeutic effectiveness

Niemann Pick Type C (NPC) is a rare neurodegenerative lipidosis that is characterized by lipid storage in the endosomal/lysosomal system. Current treatment modalities for this devastating disease are currently non-existent due to the severe obstacles associated with accessing the central nervous system with proteins or genes. The majority of mutations causing NPC disease are missense mutations. Studies have shown that some of these mutations, including the most prevalent I1061T allele, result in the production of proteins that may be functional but are targeted for degradation due to misfolding. Furthermore, we and others have observed that overepression of the mutant proteins can rescue the disease phenotype, suggesting that upregulation of the endogenous NPC1 mutant protein is a new drug treatment modality for the disorder. We hypothesize that small chemical molecules that can increase the expression of NPC1 can be identified and thus propose the following specific aims: 1) High throughput screening for identification of small molecules that upregulate NPC1 expression, utilizing the MLSCN (Molecular Libraries Screening Center Network) compound collection for drug-like small chemical molecules, and 2) Characterize and confirm positive hits, using in vitro assays, for their therapeutic potential in the treatment of NPC1 disease. These studies will result in the identification of candidate compounds that will ultimately be evaluated in vivo in an NPC mouse model to determine their therapeutic potential and future drug development.

尼曼匹克C型（NPC）是一种罕见的神经退行性脑白质病，其特征在于内体/溶酶体系统中的脂质储存。目前这种毁灭性疾病的治疗方式目前尚不存在， 与蛋白质或基因进入中枢神经系统相关的严重障碍。导致NPC疾病的大多数突变是错义突变。研究表明，这些突变中的一些，包括最普遍的I1061 T等位基因，导致蛋白质的产生，这些蛋白质可能是功能性的，但由于错误折叠而被靶向降解。此外，我们和其他人已经观察到突变蛋白的抑制可以挽救疾病表型，这表明内源性NPC 1突变蛋白的上调是该疾病的一种新的药物治疗方式。我们 假设可以鉴定出能够增加NPC 1表达小化学分子，并因此提出以下具体目标： 1)利用MLSCN（分子库筛选中心网络）药物样小化学分子化合物库进行高通量筛选，以鉴定上调NPC 1表达的小分子，以及 2)使用体外试验表征并确认阳性命中，以确定其在NPC 1疾病治疗中的治疗潜力。 这些研究将导致候选化合物的鉴定，这些化合物最终将在NPC小鼠模型中进行体内评价，以确定其治疗潜力和未来的药物开发。