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

基本信息

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
项目类别：
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

项目摘要

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 C 型尼曼-匹克病 (NPC) 是一种常染色体隐性遗传的神经退行性疾病。 95%的患者会发生NPC1基因突变，产生的NPC1蛋白被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在细胞内运输。那里目前尚无 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满足鼻咽癌患者的需求。本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。整体该提案的目标是识别和优化调节自噬、改善 NPC 的小分子体外表型，恢复体内脂质稳态，同时延长寿命。这样做的理由研究发现自噬调节的多种机制，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。中央这项研究的假设是调节自噬的小分子可以减轻胆固醇积累并延长NPC小鼠的寿命。但目前尚不清楚自噬的机制是什么调制是最有益的，这个问题将成为本研究的中心焦点鉴定可改善 NPC 表型的自噬调节剂。这种方法是创新的，因为它脱离了开发自噬调节剂然后探索其在NPC和中的作用的现状相反，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自噬调节机制。将使用质谱成像作为确定调节剂机制并评估自噬调节剂体内功效的新方法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。这拟议的研究意义重大，因为它将确定哪种自噬调节机制最重要对鼻咽癌有益，它将提供对鼻咽癌有效的新型小分子自噬调节剂，并且它将为无需标记探针的体内小分子机制评估提供新策略。这些进展将极大地有助于实现为鼻咽癌患者带来新的治疗选择的长期目标。