Tau-mediated synaptic dysfunction in age-related neurodegenerative diseases

年龄相关神经退行性疾病中 Tau 介导的突触功能障碍

基本信息

批准号：
10729927
负责人：
Audrey Weber
金额：
$ 4.07万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-07 至 2025-09-06
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10729927
关键词：
Action Potentials Affinity Age Aging Alzheimer&apos s Disease Axon Biochemical Biochemistry Biological Biological Models Brain Brain region Cell model Cells Cellular biology Communities Data Dendrites Dendritic Spines Disease Disease Progression Disease model Electrophysiology (science)Event Exhibits Experimental Designs Experimental Models Exposure to Functional disorder Glutamate Receptor Goals Human Impaired cognition Link MAPT gene Maintenance Mass Spectrum Analysis Mediating Memory Methods Microscopy Microtubules Modeling Molecular Nerve Degeneration Neurofibrillary Tangles Neurons Pathologic Pathology Pathway interactions Patients Phase Phenotype Population Positioning Attribute Postdoctoral Fellow Process Proteins Proteome Proteomics Research Research Personnel Sampling Severities Signal Pathway Specificity Structure Synapses Tauopathies Techniques Temporal Lobe Testing Therapeutic Tissues Training Universities Validation Vertebral column Work age related age related neurodegeneration aging brain cell type cognitive function cohort density entorhinal cortex experimental study human data human disease human model interest morphometry mouse model multi-electrode arrays negative affect network dysfunction neuronal cell body new therapeutic target normal aging novel postsynaptic pre-clinical preservation religious order study skills success tau Proteins tau aggregation tau mutation therapeutic target

项目摘要

Neurofibrillary tangles (NFTs) of the microtubule-associated protein tau are a universal feature of the aging brain. The extent of tau pathology throughout the brain correlates with both synapse loss and severity of cognitive impairment in age-related tauopathies. The ability to maintain cognitive function with a brain accumulating NFTs relies on the preservation and maintenance of synaptic networks. Therefore, understanding the mechanism by which tau contributes to network and synapse vulnerability is critical for developing preventative therapeutics. The goal of this proposal is to determine the cellular mechanism(s) by which pathologic tau drives neuronal network dysfunction. The experiments proposed in this application will uncover these mechanisms and provide intellectual and technical training for a successful transition into a postdoctoral position. The F99 phase (Aim 1) will test mechanistic cell biological hypotheses to better define how abnormal tau accumulation induces synaptic dysfunction, while providing opportunity to develop intricate experimental design and execution skills through cutting-edge biochemistry, microscopy, and electrophysiology techniques. The K00 phase (Aim 2) will build upon the F99 studies with computational strategies to integrate proteomics data from humans and experimental models to identify co-existing molecular changes that are highly relevant to age-related tauopathies.

微管相关蛋白 tau 的神经原纤维缠结 (NFT) 是衰老大脑的普遍特征。整个大脑 tau 蛋白病理学的程度与突触损失和认知能力严重程度相关与年龄相关的tau蛋白病的损害。通过大脑积累 NFT 来维持认知功能的能力依赖于突触网络的保存和维护。因此，了解该机制 tau 蛋白导致网络和突触脆弱性对于开发预防性疗法至关重要。该提案的目标是确定病理性 tau 驱动神经元的细胞机制网络功能障碍。本申请中提出的实验将揭示这些机制并提供成功过渡到博士后职位的智力和技术培训。 F99 阶段（目标 1）将测试机制细胞生物学假设，以更好地确定异常 tau 积累如何诱导突触功能障碍，同时提供机会来发展复杂的实验设计和执行技能尖端的生物化学、显微镜和电生理学技术。 K00 阶段（目标 2）将建立在 F99 研究采用计算策略来整合来自人类和实验的蛋白质组学数据模型来识别与年龄相关的 tau蛋白病高度相关的共存分子变化。