HTS of Rab9 promoter activators

描述(由申请人提供)：具有神经病理的溶酶体期疾病(LSD)的治疗方式，如Niemann-Pick C型疾病(NPC)，目前尚不存在，因为与利用蛋白质或基因进入中枢神经系统相关的严重障碍，此外，这些罕见的孤儿疾病没有引起制药公司的兴趣，进一步导致任何形式的治疗缺乏前景。我们已经开发了一种新的范式，称为“孤儿受体旁路疗法”(Orbyt)，以解决这些疾病。这一范式假设内源性“抑制”蛋白的存在，其表达可以显著改善LSD的发病机制。目标是识别/发现能够调节这些蛋白质表达的小化合物，并为这些破坏性疾病提供一种新的治疗方式。我们先前已经证明，小GTPase蛋白Rab9满足这一要求，并可以作为鼻咽癌表型的抑制因子。因此，我们建议首先开展： *利用MLSCN(分子文库筛选中心网络)化合物收集类药物小分子，高通量筛选鉴定上调Rab9表达的小分子，以及 *使用体外试验鉴定和确认阳性HITS在治疗NPC1疾病方面的治疗潜力， *这些研究将确定候选化合物，最终将在NPC小鼠模型中进行活体评估，以确定它们的治疗潜力和未来的药物开发。

DESCRIPTION (provided by applicant): Treatment modalities for lysosomal stage diseases (LSDs) with neuropathology such as Niemann-Pick Type C Disease (NPC) are currently non-existent due to the severe obstacles associated with accessing the central nervous system with proteins or genes, Also, these rare orphan disorders do not attract the interest of pharmaceutical companies, further contributing to the lack of prospects for any form of treatment of therpy. We have developed a new paradigm, termed "Orphan Receptor Bypass Therapy" (ORByT), to address these disorders. This paradigm posits the existence of endogenous "suppressor" proteins whose expression can dramatically improve LSD pathogenesis. The goal is the identification/discovery of small chemical compounds that can modulate the expression of these proteins and provide a new treatment modality for these devastating disorders. We have previously shown that the small GTPase protein Rab9 meets this requirement and can act as suppressor of the NPC phenotype. Thus, we propose to first carry out: * High throughput screening for identification of small molecules that upregulate Rab9 expression, utilizing the MLSCN (Molecular Libraries Screening Center Network) compound collection for drug-like small chemical molecules, and * Characterize and confirm positive hits, using in vitro assay, 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.