Development of autophagy modulators for evaluation as a therapeutic strategy for Niemann-Pick Type C

自噬是一种细胞内稳态途径，与许多疾病有关。其中一 C型尼曼-匹克病（Niemann-Pick disease type C，NPC）是一种常染色体隐性遗传的神经退行性疾病。 NPC 1基因突变发生在95%的患者中，所产生的NPC 1蛋白质错误折叠和降解 或不再能够促进脂质和胆固醇通过溶酶体的细胞内运输。那里 目前还没有FDA批准的NPC治疗方法，因此迫切需要开发有效的治疗方法 以满足NPC患者的需求。这项研究的长期目标是通过以下方式满足这一需求： 开发恢复体内脂质稳态的小分子自噬调节剂。整体 该提案的目的是鉴定和优化调节自噬的小分子，改善NPC， 表型，并恢复体内脂质稳态，同时也延长寿命。这样做的理由 研究表明，自噬调节的各种机制，包括早期抑制，晚期抑制， 抑制和激活在NPC模型中具有潜在的治疗益处。中央 这项研究的假设是，调节自噬的小分子将减轻胆固醇 并延长NPC小鼠的寿命。然而，自噬的机制仍不清楚， 调制是最有益的，这个问题将是本研究的一个中心焦点，通过无偏见的 鉴定改善NPC表型的自噬调节剂。这种方法是创新的，因为它 从开发自噬调节剂并探索其在NPC中的作用的现状出发， 相反，使用表型筛选来鉴定对NPC表型具有积极影响的调节剂， 随后确定自噬调节的机制。将使用质谱成像 作为一种新的方法来确定调节剂机制和评估体内自噬调节剂的功效 通过分析蛋白质和脂质的变化，这也将有助于识别生物标志物。的 拟议的研究是重要的，因为它将确定哪种自噬调节机制是最重要的。 在NPC中有益，它将提供在NPC中有效的新型小分子自噬调节剂，并且它将 为在无标记探针的情况下评估小分子机制提供了新的策略。这些 这些进展将大大有助于为NPC患者带来新的治疗选择的长期目标。

Autophagy is a cellular homeostasis pathway that has been implicated in numerous diseases. One of these diseases, Niemann-Pick disease type C (NPC), is an autosomal recessive, neurodegenerative disorder. Mutations in the NPC1 gene occur in 95% of patients, and the resultant NPC1 protein is misfolded and degraded or no longer capable of facilitating intracellular trafficking of lipids and cholesterol through the lysosome. There is currently no FDA-approved therapy for NPC, and thus there is a critical need to develop effective therapeutics to meet the needs of NPC patients. The long-term goal of this research is to address this need through the development of small-molecule autophagy modulators that restore lipid homeostasis in vivo. The overall objective of this proposal is to identify and optimize small molecules that modulate autophagy, improve the NPC phenotype in vitro, and restore lipid homeostasis in vivo while also extending life span. The rationale for this research is that various mechanisms of autophagy modulation, including early-stage inhibition, late-stage inhibition, and activation, have been reported to have potential therapeutic benefit in models of NPC. The central hypothesis of this research is that small molecules that modulate autophagy will alleviate cholesterol accumulation and extend life span of NPC mice. However, it is still unclear what mechanism of autophagy modulation is most beneficial, and this question will be a central focus of this research through unbiased identification of autophagy modulators that improve the NPC phenotype. This approach is innovative because it departs from the status quo of developing autophagy modulators and then exploring their effects in NPC and instead uses phenotypic screens to identify modulators that have a positive impact on NPC phenotypes with subsequent determination of the mechanism of autophagy modulation. Mass spectrometry imaging will be used as a novel method to determine modulator mechanism and to evaluate efficacy of autophagy modulators in vivo through the analysis of protein and lipid changes, which will also aid in the identification of biomarkers. The proposed research is significant because it will identify which mechanism of autophagy modulation is most beneficial in NPC, it will provide novel, small-molecule autophagy modulators with efficacy in NPC, and it will provide new strategies for the assessment of small-molecule mechanism in vivo without labeled probes. These advances will greatly contribute to the long-term goal of bringing new therapeutic options to NPC patients.