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。这其中的一个 疾病，尼曼-皮克病C型(NPC)，是一种常染色体隐性遗传的神经退行性疾病。 NPC1基因的突变发生在95%的患者中，由此产生的NPC1蛋白错误折叠和降解 或者不再能够通过溶酶体促进细胞内脂类和胆固醇的运输。那里 目前还没有FDA批准的鼻咽癌治疗方法，因此迫切需要开发有效的治疗方法 以满足鼻咽癌患者的需求。这项研究的长期目标是通过 体内恢复脂质动态平衡的小分子自噬调节剂的发展。整体而言 这项建议的目的是寻找和优化调节自噬的小分子，改善鼻咽癌 体外表型，并在体内恢复脂类平衡，同时延长寿命。这样做的理由是 研究表明，自噬调节的各种机制，包括早期抑制、晚期抑制 据报道，抑制和激活在鼻咽癌模型中具有潜在的治疗益处。中环 这项研究的假设是，调节自噬的小分子将缓解胆固醇 蓄积，延长鼻咽癌小鼠寿命。然而，目前仍不清楚自噬的机制。 调制是最有益的，这个问题将是本研究的中心焦点，通过无偏见 可改善鼻咽癌表型的自噬调节剂的鉴定。这种方法是创新的，因为它 从自噬调节子的发展现状出发，探讨其在鼻咽癌和鼻咽癌中的作用 取而代之的是使用表型筛选来识别对NPC表型有积极影响的调节剂 随后确定了自噬调节的机制。将使用质谱学成像 作为一种新的方法来确定自噬调节剂的作用机制并评价其在体内的疗效 通过分析蛋白质和血脂的变化，这也将有助于识别生物标志物。这个 提出的研究具有重要意义，因为它将确定自噬调节的哪种机制最多 对鼻咽癌有益，它将为新的小分子自噬调节剂提供对鼻咽癌有效的药物，它将 为无标记探针的体内小分子机制的评估提供新的策略。这些 进展将极大地促进为鼻咽癌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.