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.

抽象的 自噬是一种细胞稳态途径，与许多疾病有关。 这些疾病之一是尼曼派克型C型（NPC），是一种常染色体隐性， 神经退行性疾病。 NPC1基因的突变发生在95％的患者中，并且 由此产生的NPC1蛋白被错误折叠和降解或不再能够促进 通过溶酶体对脂质和胆固醇的细胞内运输。目前没有FDA- 批准的NPC疗法，因此有迫切需要开发有效的治疗剂 满足NPC患者的需求。这项研究的长期目标是解决这一需求 通过开发恢复脂质的小分子自噬调节剂 体内稳态。该提案的总体目的是识别和优化小型 调节自噬，在体外改善NPC表型并恢复脂质的分子 体内体内稳态，同时还延长了寿命。这项研究的理由是各种各样的 自噬调制机制，包括早期抑制，晚期抑制和 据报道，激活在NPC模型中具有潜在的治疗益处。这 这项研究的中心假设是调节自噬的小分子会减轻 胆固醇的积累并延长NPC小鼠的寿命。但是，仍然不清楚什么 自噬调制机制是最有益的，这个问题将是一个核心重点 通过无偏见的自噬调节剂来改善NPC的研究 表型。这种方法具有创新性，因为它偏离了发展的现状 自噬调节器，然后探索其在NPC中的效果，而是使用表型 筛选以识别对NPC表型产生积极影响的调节器，随后 确定自噬调制机制。质谱成像将是 用作确定调节器机制并评估功效的新方法 通过分析蛋白质和脂质变化，体内自噬调节剂，这也将 帮助识别生物标志物。拟议的研究很重要，因为它将 确定哪种自噬调制机制在NPC中最有益，它将提供 新颖的小分子自噬调节剂在NPC中具有功效，它将提供新的 在体内评估小分子机制的策略，没有标记的探针。 这些进步将极大地有助于带来新的治疗选择的长期目标 给NPC患者。