The Role of the Tau in Homeostatic Scaling and Mechanisms of Alzheimer's Disease

Tau 在阿尔茨海默病稳态调节和机制中的作用

• 批准号: 10604298
• 负责人: Meaghan O'Malley Morris
• 金额: $ 17.12万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10604298
• 关键词: AMPA Receptors; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease therapy; Amyloid beta-Protein; Area; Award; Behavior; Binding; Biological Process; Biology; Biometry; Coupled; Data; Development; Disease; Foundations; Future; Goals; Hippocampus; Human; Imaging Techniques; Induced pluripotent stem cell derived neurons; Investigation; Knock-out; Knockout Mice; Knowledge; Label; Link; Long-Term Depression; MAPT gene; Mass Spectrum Analysis; Mentorship; Mission; Modeling; Molecular; Mus; Neurodegenerative Disorders; Neuronal Plasticity; Neurons; Organism; Outcome; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Pattern; Physicians; Process; Proteins; Protocols documentation; Public Health; Rattus; Regulation; Research; Resistance; Role; Scientist; Seizures; Synapses; Synaptic plasticity; Testing; Therapeutic; Training; United States National Institutes of Health; Universities; Vertebral column; Work; abeta oligomer; career; collaborative environment; disability; fluorescence imaging; improved; induced pluripotent stem cell; innovation; insight; knock-down; mouse model; neuropathology; new therapeutic target; novel; novel therapeutic intervention; postsynaptic; stem cell model; tau Proteins; tau function; tau interaction; therapeutically effective; trafficking

Project Summary Little is unknown about the mechanisms involved in the regulation of neuronal network activity by the microtubule associated protein tau, a key pathogenic protein in Alzheimer's disease (AD). The long term goal is to develop an independent career as a neuropathologist and a molecular neuroscientist integrating observations from human neuropathology with molecular understanding to gain new insights into AD pathogenesis and therapeutic strategies. This research is initially focused on how tau regulates neuronal activity and how this regulation relates to mechanisms of AD. Preliminary studies show tau localization is regulated by homeostatic scaling, a critical form of synaptic plasticity implicated in AD. The overall objectives for this application are to (i) elucidate the role of tau in homeostatic scaling, (ii) define alterations in the molecular interactions of tau during homeostatic scaling, and (iii) determine the role of homeostatic scaling in the post-synaptic alterations of tau and AMPA receptors in culture models of AD. The central hypothesis of this proposal is that homeostatic scaling pathways are regulated by tau and are utilized by Aβ to create post- synaptic changes in AD. This hypothesis will be tested using live neuron fluorescent imaging of tau and AMPA receptors, inhibition or knock-down of tau and proteins critical to homeostatic scaling, and mass spectrometry analysis of tau interacting proteins under homeostatic scaling conditions. The rationale for this project is that improved understanding of tau functions and their relationship to the pathogenesis of AD may lead to new avenues of investigation for AD therapies while offering an opportunity to establish the candidate's independence as a molecular neuroscientist. This effort will directly involve the mentorship of Dr. Richard Huganir, an expert neuroscientist in the field of molecular mechanisms synaptic plasticity, and will take advantage of the rich and collaborative environment of Alzheimer's disease research at Johns Hopkins University. This work will build on the candidate's strong foundation in neurodegenerative disease pathology and research, which will be supplemented by training in synaptic biology, imaging techniques, human induced pluripotent stem cells (iPSCs), and biostatistical analysis, areas critical to the proposed work and to future investigations. The proposed research is innovative because it defines novel roles and interactions of tau regulated by neuronal activity, and it directly tests the contribution of homeostatic scaling to AD-related synaptic changes. The proposed research is significant because it will provide insight into novel biologic functions and interactions of tau, and their relationship to AD pathogenesis. Ultimately, knowledge of these mechanisms may elucidate of the contribution of tau to sporadic AD and lead to novel therapeutic strategies.

项目摘要 关于调节神经元网络活性的机制，几乎一无所知 微管相关蛋白tau，这是阿尔茨海默氏病（AD）中的关键致病蛋白。长期目标 是作为神经病理学家和分子神经科学家融合的独立职业 从人类神经病理学的观察和分子理解中的观察，以获取对AD的新见解 发病机理和治疗策略。这项研究最初集中于tau如何调节神经元 活动以及该调节与AD机制的关系。初步研究表明，tau定位是 由稳态缩放调节，一种与AD有关的突触可塑性的关键形式。总体目标 对于此应用，（i）阐明tau在体内稳定性缩放中的作用，（ii）定义改变的变化 tau在体内缩放期间的分子相互作用，（iii）确定稳态缩放的作用 AD培养模型中Tau和AMPA受体的突触后变化。中心假设 建议是，稳态缩放途径受tau的调节，并被Aβ用于创建 AD的突触变化。该假设将使用TAU和AMPA的实时神经元荧光成像进行检验 受体，对tau的抑制作用或对稳态缩放至关重要的蛋白质的抑制作用或蛋白质 在体内缩放条件下对Tau相互作用蛋白的分析。这个项目的理由是 对tau功能的理解及其与AD发病机理的关系有所提高可能导致新的 用于广告疗法的投资途径，同时提供建立候选人的机会 独立为分子神经科学家。这项努力将直接涉及理查德博士的指导。 Huganir是分子机制领域的专家神经科学家，并将采用 约翰·霍普金斯（Johns Hopkins）阿尔茨海默氏病研究的丰富和协作环境的优势 大学。这项工作将基于候选人在神经退行性疾病病理学的强大基础上 和研究，将通过突触生物学，成像技术，人类诱导的培训来补充 多能干细胞（IPSC）和生物统计分析，对拟议工作至关重要的领域和未来 调查。拟议的研究具有创新性，因为它定义了tau的新作用和相互作用 受神经元活动调节，它直接测试了稳态缩放对广告相关的贡献 突触变化。拟议的研究很重要，因为它将提供对新型生物学的见解 Tau的功能和相互作用及其与AD发病机理的关系。最终，对这些知识 机制可以阐明Tau对零星AD的贡献，并导致新的治疗策略。