权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Linking tau proteostasis with neuronal activity in FTD

将 tau 蛋白稳态与 FTD 中的神经元活动联系起来

基本信息

批准号：
10011925
负责人：
Li Gan
金额：
$ 204.36万
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/10011925
关键词：
Address Advisory Committees Affect Alzheimer&apos s Disease Animal Model Autophagocytosis Brain CRISPR interference Candidate Disease Gene Cells Clinical Clustered Regularly Interspaced Short Palindromic Repeats Communication Communities Complex Cultured Cells Data Data Analyses Development Disease Ensure Experimental Designs Failure Feedback Frontotemporal Lobar Degenerations Gene Expression Generations Heterogeneity Human In Vitro Infrastructure Libraries Link Mediating Mutation Nerve Degeneration Neuronal Dysfunction Neurons Pathogenesis Pathogenicity Pathology Pathway interactions Patients Post-Translational Protein Processing Process Proteins Proteomics Reagent Research Resources Role Sampling Shapes Structure Tauopathies Technology Testing Toxic effect United States National Institutes of Health Validation Vision Work data integration data sharing experience extracellular functional outcomes genome-wide human data human tissue hyperphosphorylated tau in vivo induced pluripotent stem cell innovative technologies insight member multi-electrode arrays mutant novel novel therapeutics patch clamp proteostasis screening synaptic function synergism tau Proteins tau mutation transcriptome uptake

项目摘要

ABSTRACT — OVERALL COMPONENT Neurodegenerative tauopathies, including Alzheimer's disease (AD) and frontotemporal lobar degeneration with tau inclusions (FTLD-tau), are characterized by tau inclusions of hyperphosphorylated tau. However, which tau species are pathogenic and how they induce neuronal dysfunction remain elusive. We hypothesize that there is a crosstalk between tau proteostasis imbalance, in the form of intracellular accumulation and intercellular spread, and neuronal dysfunction. Our vision statement is: Linking tau proteostasis with neuronal activity in FTD. We propose to use a combination of unbiased discovery and focused hypothesis- driven approaches to dissect the mechanistic connection. The Center, composed of three projects (P1–P3) and five cores (MS, CRISPR, Human, Data and Admin), aims at addressing the following fundamental questions in tau pathogenesis. In Specific Aim 1, we will address what causes tau to accumulate and spread in FTD. P1 and P3 will work together with MS core to dissect whether aberrant post-translational modifications (PTMs) are critically involved in modulating tau's failure to be degraded and subsequent release. P1, P2 and P3 will work together with CRISPR core to dissect the uptake and seeding mechanisms, using a combination of hypothesis-driven candidate approaches and genome-wide CRISPRi/a library screening. P1, P2 and P3 will work together with the Human core to validate the findings from iPSC neurons in human tissues. In Specific Aim 2, we will determine how tau proteostasis imbalance induces neuronal dysfunction. Despite large amount of evidence supporting the accumulation and spread of tau pathology in animal models and in cultured cells, little is known about the mechanisms behind this toxicity and their direct impact on neuronal/synaptic function in human neurons. P1 and P2 will work together to define the effects of FTD mutations on human neuronal activity both at the single-cell and network levels using whole-cell patch clamp and multi-electrode array (MEA), respectively. P3 will work with P1 and P2 to examine if altered autophagy affects neuronal activity. P1, P2 and the CRISPR core will work together to examine the functional effects of tau oligomerization. In Specific Aim 3, we will examine how neuronal activity modulates tau proteostasis. Both in vitro and in vivo studies showed that the release of tau is activity-dependent, supporting a feedback mechanism by which aberrant neuronal activity further alters tau proteostasis. P1 will work with the MS and CRISPR cores to dissect the mechanisms underlying the activity-dependent tau release. P1 and P2 will work synergistically to address if and how neuronal activity could affect the uptake (P2) or seeding (P1) of pathogenic tau. P3 will work with P1 and P2 to determine how altering neuronal activity modulates different autophagic pathways. In summary, the Center is strategically structured to maximize conceptual and technological synergies, full data integration and cross-validation. We anticipate discovery of novel insights into mechanisms underlying tau toxicity, generation of novel resources and reagents, and development of innovative technology platforms.

抽象-整体组件神经退行性疾病，包括阿尔茨海默病(AD)和额颞叶变性具有tau包裹体(FTLD-tau)，以过度磷酸化的tau包裹体为特征。然而，哪些tau物种是致病的，它们是如何导致神经元功能障碍的仍不清楚。我们假设在以细胞内堆积形式存在的tau蛋白平衡失衡和细胞间扩散和神经元功能障碍。我们的愿景是：将tau蛋白平衡与 FTD中的神经元活动。我们建议结合无偏见的发现和聚焦的假设- 驱动的方法来剖析机械连接。中心，由三个项目(P1-P3)组成和五个核心(MS、CRISPR、Human、Data和Admin)，旨在解决以下基本问题关于tau发病机制的问题。在具体目标1中，我们将解决导致tau累积和扩散的原因。在FTD中。P1和P3将与MS CORE合作，剖析异常的翻译后修改 (PTM)在调节tau不能被降解和随后的释放中起着至关重要的作用。小一、小二和 P3将与CRISPR核心一起工作，使用组合来剖析吸收和播种机制假设驱动的候选方法和全基因组CRISPRi/a文库筛选。P1、P2和P3将与人类核心组织合作，验证来自人类组织中IPSC神经元的发现。具体而言目的2，我们将确定tau蛋白平衡失衡如何导致神经元功能障碍。尽管金额很大支持tau病理在动物模型和培养细胞中积累和传播的证据，人们对这种毒性背后的机制及其对神经元/突触功能的直接影响知之甚少。在人类神经元中。P1和P2将共同确定FTD突变对人类神经元的影响使用全细胞膜片钳和多电极阵列在单细胞和网络水平上的活动 (Mea)，分别。P3将与P1和P2一起研究改变的自噬是否会影响神经元的活动。P1， P2和CRISPR核心将共同研究tau齐聚的功能效应。具体而言目的3，我们将研究神经元活动如何调节tau蛋白稳态。体外和体内研究表明tau的释放是活性依赖的，支持一种反馈机制，通过这种反馈机制神经元活动进一步改变tau蛋白平衡。P1将与MS和CRISPR核心合作，剖析依赖活性的tau释放的潜在机制。P1和P2将协同工作以解决以下问题以及神经元活动如何影响致病tau的摄取(P2)或播种(P1)。P3将与P1配合使用和P2，以确定改变神经元活动如何调节不同的自噬途径。总而言之，中心采用战略性结构，以最大限度地提高概念和技术协同效应、全面数据集成和交叉验证。我们期待着对tau毒性、生成的潜在机制的新见解的发现。新资源和试剂的开发，以及创新技术平台的开发。