HTS of NPC1 promoter activators

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脂质病，其特征是内体飞体系统的脂质储存。由于携带蛋白质或基因进入中枢神经系统存在严重障碍，目前尚无针对这种毁灭性疾病的现有治疗方法。大多数导致鼻咽癌疾病的突变是错义突变。研究表明，其中一些突变，包括最普遍的ho61T等位基因，导致蛋白质的产生，这些蛋白质可能是功能性的，但由于错误折叠而成为降解的目标。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，这表明上调内源性NPC1突变蛋白是一种新的药物治疗方式。我们假设可以发现增加NPC1表达的小化学分子，并提出以下具体目标：1)利用MLSCN（分子文库筛选中心网络）化合物收集药物样小化学分子，对上调NPC1表达的小分子进行高通量筛选；2)利用体外试验表征和确认阳性命中，以确定其在治疗NPC1疾病中的治疗潜力。这些研究将鉴定出候选化合物，最终将在NPC小鼠模型中进行体内评估，以确定其治疗潜力和未来的药物开发。

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.