Defining the role of autophagy in human neurodegeneration and neuronal aging

定义自噬在人类神经退行性变和神经元衰老中的作用

• 批准号: 401380638
• 负责人: Dr. Johannes Jungverdorben, Ph.D.
• 金额: --
• 依托单位: Memorial Sloan Kettering Cancer Center
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/401380638?language=en
• 关键词: Defining; role; autophagy; human; neurodegeneration

One of the major shortcomings of animal and human cancer stem cell line-based models is the limited success in predicting outcomedisease-relevant outcomes when applied to the human CNS. Accordingly, there is a huge need for defining mechanistic insights directly in the relevant human neuronsneuron subtypes affected by disease. This is especially the case infor the fieldprocess of autophagy, a processwhich is important for neurogenesis, neurodegeneration and neuronal aging. My studies will pursue the following aims using human pluripotent stem cell (hPSC)-derived neurons as model system:i) I will generate genetically engineered hPSCs lines that allow a tight control of autophagic flux at any given time point of neural development and maturation. ii) I will analyze the effect of inhibiting autophagy on protein aggregation in pure neurons of defined identity and establish profiles of the aggregating proteome specific for each neuronal subtype by cell fractionation and subsequent SILAC-mass spectrometry.iii) Using progerin-induced neuronal aging as a reference for specific aging hallmarks, I will assess the capacity of autophagy inhibition on promoting aging-related alterations in human neurons as well as autophagythe induction for the reversion of thoseautophagy in an effort to reverse aging hallmarks and as a possible rejuvenation strategy.The proposed approach will enable the study of human neurogenesis, mechanisms of protein aggregation in mature neurons of specific identity and the contribution of autophagy on the cellular hallmarks of neuronal aging. I expect that the project will add significant knowledge on how autophagy contributes to human neurogenesis and, how it impacts neuron subtype-specific protein aggregation profiles, and on how a decline in autophagy may promote hallmarks of neuronal aging. Finally, I anticipate that the results will make a valuable contribution to our understanding of healthy neuronal homeostasis during human aging. and point to candidate therapeutic pathways in neurodegenerative disease

基于动物和人类癌症干细胞系的模型的主要缺点之一是当应用于人类CNS时，在预测结果疾病相关结果方面的成功有限。因此，有一个巨大的需求，直接在受疾病影响的相关人类神经元神经元亚型中定义机制的见解。自噬是一个对神经发生、神经退行性变和神经元老化都很重要的过程。我的研究将使用人多能干细胞（hPSC）衍生的神经元作为模型系统追求以下目标：i）我将产生基因工程化的hPSC系，其允许在神经发育和成熟的任何给定时间点严格控制自噬通量。ii）我将分析抑制自噬对确定身份的纯神经元中蛋白质聚集的影响，并通过细胞分级分离和随后的SILAC-质谱法建立对每种神经元亚型特异性的聚集蛋白质组的谱。我将评估自噬抑制促进衰老的能力-人类神经元的相关改变以及自噬诱导这些自噬的逆转，以逆转衰老的标志，所提出的方法将使人类神经发生的研究，在成熟的神经元的特定身份和自噬的神经元老化的细胞标志的贡献的蛋白质聚集的机制。我希望该项目将增加关于自噬如何促进人类神经发生的重要知识，以及它如何影响神经元亚型特异性蛋白质聚集谱，以及自噬下降如何促进神经元衰老的标志。最后，我预计这些结果将为我们理解人类衰老过程中健康的神经元稳态做出有价值的贡献。并指出了神经退行性疾病的候选治疗途径