HTS of NPC1 promoter activators

NPC1 启动子激活剂的 HTS

• 批准号: 7929269
• 负责人: YIANNIS A IOANNOU
• 金额: $ 4.24万
• 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/7929269
• 关键词: Affect; Alleles; Brain; Chemicals; Collection; Disease; Future; Genes; Hereditary Disease; Lipids; Lipoidosis; Missense Mutation; Modality; Molecular Bank; Mutation; Nerve Degeneration; Neuraxis; Neurologic; Pharmaceutical Preparations; Production; Proteins; Screening procedure; Supraoptic Vertical Ophthalmoplegia; System; Therapeutic; Up-Regulation; candidate identification; disease phenotype; drug development; high throughput screening; in vitro Assay; in vivo; mouse model; mutant; novel strategies; overexpression; promoter; public health relevance; small molecule

DESCRIPTION (provided by applicant): Niemann Pick Type C (NPC) is a rare neurodegenerative lipidosis that is characterized by lipid storage in the endosomalflysosomal 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 ho61T 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 overexpression 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. PUBLIC HEALTH RELEVANCE: Diseases that affect the brain are currently difficult if not impossible to treat. We have developed a novel approach to treat devastating genetic diseases with neurological involvement that are currently untreatable by utilizing molecules that can upregulate the expression of the mutant protein providing partial correction of the disease phenotype.

描述（由申请人提供）：尼曼匹克C型（NPC）是一种罕见的神经退行性结节病，其特征是内体-溶酶体系统中的脂质储存。由于与蛋白质或基因进入中枢神经系统相关的严重障碍，目前这种毁灭性疾病的治疗方式目前尚不存在。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ho 61 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过表达可以挽救疾病表型，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可以增加NPC 1表达的小化学分子，因此提出了以下具体目标：1）利用MLSCN进行高通量筛选以鉴定上调NPC 1表达的小分子（分子库筛选中心网络）药物样小化学分子的化合物收集，和2）使用体外测定表征和确认阳性命中，因为它们在治疗NPC 1疾病中的治疗潜力。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。 公共卫生相关性：影响大脑的疾病是目前很难，如果不是不可能治疗。我们已经开发了一种新的方法来治疗破坏性的遗传疾病与神经系统的参与，目前无法治疗的分子，可以上调突变蛋白的表达，提供部分纠正的疾病表型。