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: 10372057
• 负责人: Leslie N Aldrich
• 金额: $ 38.56万
• 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 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10372057
• 关键词: Address; Adolescence; Affect; Animals; Autophagocytosis; Biological Assay; Biological Process; Biology; Brain; Cell Death; Cells; Cessation of life; Child; Cholesterol; Clinical; Communities; Complex; Development; Disease; Disease Progression; Dose; Drug Kinetics; Evaluation; FDA approved; Fibroblasts; Gene Expression; Gene Expression Profiling; Genetic Diseases; Goals; Health; Homeostasis; Image; In Vitro; Label; Lead; Lipids; Liver; Longevity; Lysosomes; Mass Spectrum Analysis; Measures; Methods; Modeling; Mus; Mutant Strains Mice; Mutation; NPC1 gene; National Institute of Neurological Disorders and Stroke; Neurodegenerative Disorders; Organ; Pathway interactions; Patients; Permeability; Phenotype; Property; Protein Analysis; Proteins; Proteomics; Public Health; Recycling; Regimen; Reporting; Research; Role; Solubility; Supraoptic Vertical Ophthalmoplegia; Symptoms; Testing; Therapeutic; Therapeutic Intervention; Time; Translating; Visceral; Work; analog; animal tissue; aqueous; biomarker identification; blood-brain barrier penetration; drug discovery; drug distribution; drug efficacy; drug metabolism; efficacy evaluation; emerging adult; experimental study; improved; in vivo; in vivo evaluation; innovation; knock-down; lead optimization; lipid transport; mass spectrometric imaging; nervous system disorder; novel; novel therapeutics; overexpression; prevent; small molecule; targeted treatment; therapeutic development; therapeutically effective; tool; treatment response

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.

自噬是一种细胞稳态途径，与许多疾病有关。其中之一 疾病，Niemann-Pick型C型（NPC）是一种常染色体隐性，神经退行性疾病。 NPC1基因中的突变发生在95％的患者中，而所得的NPC1蛋白被错误折叠并降解 或不再能够通过溶酶体促进脂质和胆固醇的细胞内运输。那里 目前尚无对NPC的FDA批准疗法 满足NPC患者的需求。这项研究的长期目标是通过 在体内恢复脂质稳态的小分子自噬调节剂的开发。总体 该建议的目的是识别和优化调节自噬，改善NPC的小分子 体外表型，并在体内恢复脂质稳态，同时延长寿命。理由 研究是自噬调制的各种机制，包括早期抑制，后期 据报道，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会减轻胆固醇 积累并延长NPC小鼠的寿命。但是，目前尚不清楚自噬的机理 调制是最有益的，这个问题将是这项研究的核心重点 鉴定改善NPC表型的自噬调节剂。这种方法是创新的，因为它 偏离开发自噬调节器的现状，然后探索其在NPC和 相反 随后确定自噬调制机制。将使用质谱成像 作为确定调节器机制并评估体内自噬调节剂功效的一种新方法 通过分析蛋白质和脂质变化，这也将有助于鉴定生物标志物。这 拟议的研究很重要，因为它将确定自噬调制的哪种机制最多 它在NPC中有益，它将为NPC提供新颖的小分子自噬调节剂，并将 提供新的策略，以评估体内小分子机制，而无需标记探针。这些 进步将极大地为NPC患者带来新的治疗选择的长期目标。