Project 3: Autophagy dysfunction and neuronal activity in FTD

项目 3：FTD 中的自噬功能障碍和神经元活动

基本信息

批准号：
9292170
负责人：
ANA MARIA CUERVO
金额：
$ 29.46万
依托单位：
J. DAVID GLADSTONE INSTITUTES
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-30 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9292170
关键词：
Acetylation Address Affect Autophagocytosis Autophagosome Autopsy Axon Brain Cell physiology Chemicals Chromosome Pairing Clustered Regularly Interspaced Short Palindromic Repeats Collaborations Data Disease Electrophysiology (science)Endosomes Environment Excision Experimental Models Failure Freezing Frontotemporal Dementia Genetic Homeostasis Human Link Maintenance Mammalian Cell Mediating Molecular Chaperones Neurodegenerative Disorders Neuronal Dysfunction Neurons Pathway interactions Patients Post-Translational Protein Processing Property Proteins Proteome Proteomics Quality Control Reporter System Tauopathies Testing Toxic effect Up-Regulation Variant Work base brain tissue data integration extracellular induced pluripotent stem cell intervention effect knock-down mutant neuron loss neuronal cell body neurotoxicity protein degradation regional difference response tau Proteins tau aggregation tau mutation tau phosphorylation uptake

项目摘要

Project 3: Autophagy dysfunction and neuronal activity in FTD Ana Maria Cuervo SUMMARY This proposal investigates the interplay between pathogenic forms of tau and selective forms of autophagy in the context of frontotemporal dementia (FTD). We will coordinate the activities of this project with those of Project 1 and Project 2 to test our working hypothesis that tau-mediated toxicity in the autophagic pathways underlie the basis for the altered tau proteostasis and functional alterations observed in FTD-affected neurons. Project 3 will use cutting edge proteomics (MS Core) and genetics (CRISPR Core) in iPSC-derived neurons to investigate: 1) effect of pathogenic intra- and extracellular tau in the activity of three different forms of selective autophagy; 2) consequences of blockage of each of these forms of autophagy on neuronal activity and tau uptake. Project 3 will also utilize postmortem frozen human brain tissue from controls and FTD-tau patients (Human Core) to identify 3) changes in the properties of tau associated with autophagic compartments in control and patient brains. Assisted by the CRISPR Core, we will modulate levels of differentially tau- interacting proteins and address the effect of this intervention on autophagy and neuronal activity. Integration of data (Data Core) generated by this project with that from the other two projects in the Center will allow us to elucidate the contribution of tau toxicity on the autophagic system to the neuronal activity imbalance observed in FTD.

项目 3：FTD Ana Maria Cuervo 中的自噬功能障碍和神经元活动概括该提案研究了 tau 蛋白的致病形式与选择性形式的自噬之间的相互作用。额颞叶痴呆（FTD）的背景。我们将协调该项目的活动与项目 1 和项目 2 测试我们的工作假设，即自噬途径中 tau 介导的毒性这是在受 FTD 影响的神经元中观察到的 tau 蛋白稳态改变和功能改变的基础。项目 3 将在 iPSC 衍生的神经元中使用尖端蛋白质组学 (MS Core) 和遗传学 (CRISPR Core) 研究：1) 致病性细胞内和细胞外 tau 对三种不同形式的选择性活性的影响自噬； 2) 阻断每种形式的自噬对神经元活动和 tau 蛋白的影响吸收。项目 3 还将利用来自对照和 FTD-tau 患者的死后冷冻人脑组织 (Human Core) 识别 3) 与自噬区室相关的 tau 特性的变化控制和耐心的大脑。在 CRISPR 核心的协助下，我们将调节差异 tau 的水平相互作用的蛋白质并解决这种干预对自噬和神经元活动的影响。该项目生成的数据（数据核心）与中心其他两个项目的数据集成让我们能够阐明 tau 对自噬系统的毒性对神经元活动失衡的影响在 FTD 中观察到。