HTS of Rab9 promoter activators

描述（申请人提供）：由于与用蛋白质或基因进入中枢神经系统相关的严重障碍，目前不存在用于具有神经病理学的溶酶体期疾病（LSD）如尼曼-匹克C型疾病（NPC）的治疗方式。此外，这些罕见的孤儿疾病没有吸引制药公司的兴趣，这进一步导致缺乏治疗任何形式的前景。我们已经开发了一种新的范例，称为“孤儿受体旁路疗法”（ORByT），以解决这些疾病。这种模式假定存在内源性“抑制”蛋白，其表达可以显着改善LSD发病机制。目标是鉴定/发现可以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新的治疗方式。我们以前已经表明，小GTdR蛋白Rab 9符合这一要求，可以作为抑制剂的NPC表型。因此，我们建议首先开展： * 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Rab 9表达的小分子， * 使用体外试验表征并确认阳性命中物在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。

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.