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：
10011929
负责人：
ANA MARIA CUERVO
金额：
$ 31.95万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
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 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10011929
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 Functional disorder Genetic Homeostasis Human Link Maintenance Mammalian Cell Mediating Molecular Chaperones Neurodegenerative Disorders Neuronal Dysfunction Neurons Pathogenicity Pathway interactions Patients Post-Translational Protein Processing Property Proteins Proteome Proteomics Quality Control Reporter Route System Tauopathies Testing Toxic effect Up-Regulation Variant brain tissue data integration extracellular induced pluripotent stem cell intervention effect knock-down mutant neuron loss neuronal cell body neurotoxicity protein degradation proteostasis 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调查了tau的致病形式与自噬的选择性形式之间的相互作用额颞痴呆（FTD）的背景。我们将协调该项目的活动项目1和项目2测试我们的工作假设，即tau介导的自噬途径中的毒性基础是在受FTD影响的神经元中观察到的改变的tau蛋白抑制剂和功能改变的基础。项目3将在IPSC衍生的神经元中使用最先进的蛋白质组学（MS Core）和遗传学（CRISPR核心）调查：1）病原性细胞内和细胞外TAU在三种不同形式的选择性的活性中的影响自噬； 2）每种形式的自噬对神经元活性和TAU的阻塞的后果吸收。项目3还将利用对照组和FTD-TAU患者的验化后冷冻人脑组织（人核）识别3）与自噬隔室相关的tau性质的变化控制和患者的大脑。在CRISPR核心的协助下，我们将调节差异的水平相互作用的蛋白质并解决了这种干预对自噬和神经元活性的影响。该项目生成的数据（数据核）与中心其他两个项目的集成将允许我们阐明TAU毒性对自噬系统对神经元活动不平衡的贡献在FTD中观察到。