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

Phase Transition-Mediated Tau Function and Dysfunction

相变介导的 Tau 功能和功能障碍

基本信息

批准号：
10674719
负责人：
Allan Chris Ferreon
金额：
$ 40万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-15 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10674719
关键词：
Acceleration Acetylation Affect Age Aging Alzheimer&apos s Disease Amyloid Fibrils Behavior Brain Diseases Cell Nucleolus Cells Coupled Disease Evolution Exhibits Filament Fluorescence Fluorescence Spectroscopy Functional disorder Gel Heparin Heterogeneity Imaging Techniques Laboratories Lead Link Liquid substance Maps Mediating Microscopy Microtubules Minor Molecular Molecular Conformation Morphology Neurodegenerative Disorders Neurons Pathologic Pathology Phase Phase Transition Phosphorylation Physiology Population Post-Translational Protein Processing Proteins Research Research Personnel Role Sodium Chloride Solid Spectrum Analysis System Tauopathies Techniques Temperature Tubulin Variant Visualization alpha synuclein biophysical techniques conformational conversion driving force experience experimental study fluorescence imaging hyperphosphorylated tau insight interest loss of function monomer novel therapeutic intervention protein TDP-43 protein aggregation recruit single molecule solid state stress granule synergism tau Proteins tau aggregation tau conformation tau dysfunction tau function tau-1

项目摘要

Project Summary Phase Transition-Mediated Tau Function and Dysfunction The proposed research will decipher the molecular mechanism of liquid-liquid phase separation (LLPS)-mediated Tau function and dysfunction. Phase-separated Tau droplets enrich tubulin and facilitate microtubule assembly (Tau function), whereas persistent droplets lead to protein aggregation. Utilizing prior extensive experience with disordered protein systems, the investigators will determine how LLPS links Tau loss-of-function and gain-of-toxic dysfunction in three stages: They will characterize how pathologic post-translational modifications (PTMs; hyperphosphorylation and hyperacetylation) modulate Tau LLPS-mediated microtubule assembly and protein aggregation (Aim 1); they will track Tau conformations that are key to both LLPS-mediated Tau function and dysfunction (Aim 2); and, they will determine how co- aggregating proteins initiate/ facilitate/ synergize Tau aggregation (Aim 3). The first Aim will utilize ensemble spectroscopy and time-lapse microscopy techniques to understand the role of PTMs in LLPS-mediated function and dysfunction. Phase transition maps of different Tau variants will be generated to characterize how different PTMs alter Tau LLPS. Effects of Tau variant co-partitioning in droplets or fibrillar aggregates on Tau function and dysfunction will also be studied. The second Aim will utilize ultrasensitive fluorescence spectroscopy techniques to track conformational conversions as monomeric Tau forms condensed droplets and as liquid droplets transform to solid states, i.e., functional (in microtubule assembled filaments) and/or dysfunctional states (amyloid fibril states). The third Aim will determine the role of co-aggregating proteins in Tau LLPS and subsequent protein aggregation. Synergistic interaction between co-phase separating proteins will be characterized. Mechanism of aggregate cross-seeding will provide insights into protein co-misfolding.

项目概要相变介导的 Tau 功能和功能障碍拟议的研究将破译液-液相的分子机制分离（LLPS）介导的 Tau 功能和功能障碍。相分离的 Tau 液滴丰富微管蛋白并促进微管组装（Tau 功能），而持久性液滴导致蛋白质聚集。利用先前在无序蛋白质系统方面的丰富经验，研究人员将确定 LLPS 如何在三个阶段将 Tau 功能丧失和毒性增加功能障碍联系起来：他们将描述病理性翻译后修饰（PTM；过度磷酸化和过度乙酰化）调节 Tau LLPS 介导的微管组装和蛋白质聚集（目标 1）；他们将追踪对两者都至关重要的 Tau 构象 LLPS 介导的 Tau 功能和功能障碍（目标 2）；并且，他们将决定如何共同聚集蛋白启动/促进/协同 Tau 聚集（目标 3）。第一个目标将利用系综光谱学和延时显微镜技术了解 PTM 在 LLPS 介导的功能和功能障碍中的作用。相变将生成不同 Tau 变体的图谱，以描述不同 PTM 如何改变 Tau LLPS。液滴或纤维状聚集体中 Tau 变异共分配对 Tau 功能的影响和功能障碍也将被研究。第二个目标将利用超灵敏荧光光谱技术来追踪单体 Tau 形成凝聚液滴和液滴时的构象转变转变为固态，即功能性（在微管组装的细丝中）和/或功能失调状态（淀粉样原纤维状态）。第三个目标将确定 Tau LLPS 中共聚集蛋白的作用和随后的蛋白质聚集。共相分离蛋白质之间的协同相互作用将被表征。聚合交叉播种机制将提供对蛋白质的见解共同错误折叠。