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

开发自噬调节剂用于评估作为 Niemann-Pick C 型治疗策略

• 批准号: 10265844
• 负责人: Leslie N Aldrich
• 金额: $ 4.12万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10265844
• 关键词: Address; Autophagocytosis; Cholesterol; Chromatography; Development; Disease; Equipment; Evaluation; FDA approved; Funding; Goals; Homeostasis; Image; In Vitro; Label; Laboratories; Lipids; Longevity; Lysosomes; Mass Spectrum Analysis; Methods; Modeling; Mus; Mutation; NPC1 gene; Neurodegenerative Disorders; Pathway interactions; Patients; Phenotype; Protein Analysis; Proteins; Reporting; Research; Research Personnel; Supraoptic Vertical Ophthalmoplegia; System; Therapeutic; Work; biomarker identification; efficacy evaluation; improved; in vivo; innovation; lipid transport; novel; novel therapeutics; small molecule; therapeutically effective

Abstract 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.

摘要 自噬是一种细胞内稳态途径，与许多疾病有关。 其中一种疾病，尼曼-皮克病C型(NPC)，是一种常染色体隐性遗传， 神经退行性疾病。NPC1基因突变发生在95%的患者中， 由此产生的NPC1蛋白错误折叠和降解，或者不再能够促进 脂类和胆固醇通过溶酶体在细胞内的运输。目前没有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来 满足鼻咽癌患者的需求。这项研究的长期目标就是解决这一需求 通过开发恢复脂质的小分子自噬调节剂 体内动态平衡。该提案的总体目标是确定和优化小型 调节自噬、改善鼻咽癌体外表型和恢复脂质的分子 体内动态平衡的同时也延长了寿命。这项研究的基本原理是不同的 自噬调节机制，包括早期抑制、晚期抑制和 已有报道在鼻咽癌模型中具有潜在的治疗作用。这个 这项研究的中心假设是，调节自噬的小分子将缓解 胆固醇蓄积和延长鼻咽癌小鼠的寿命。然而，目前仍不清楚是什么 自噬的调节机制是最有益的，这个问题将是一个中心焦点 通过公正地鉴定改善鼻咽癌的自噬调节器来完成这项研究 表型。这种方法是创新的，因为它脱离了开发的现状 自噬调节器，然后探索它们在鼻咽癌中的作用，并使用表型 筛选对鼻咽癌表型有积极影响的调节剂 自噬调节机制的确定。质谱学成像将是 作为一种新的方法来确定调节机制并评价其疗效 自噬调节剂在体内通过分析蛋白质和脂质的变化，这也将 帮助识别生物标记物。这项拟议的研究意义重大，因为它将 确定哪种自噬调节机制在鼻咽癌中最有益，它将提供 新型小分子自噬调节剂在鼻咽癌中的有效性，它将为鼻咽癌提供新的 无标记探针的体内小分子机制评估策略。 这些进展将极大地促进带来新的治疗选择的长期目标。 给鼻咽癌患者。