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Genetic Modifiers of Protein Interaction Networks in Tauopathy

Tau 病中蛋白质相互作用网络的遗传修饰

基本信息

批准号：
10654526
负责人：
Andrew EMILI
金额：
$ 59.35万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
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：
2019-08-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10654526
关键词：
Acceleration Address Affect Alleles Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease risk Amyloid Apolipoprotein E Automobile Driving Biochemical Biology Biotinylation Brain Chromatography Co-Immunoprecipitations Coupling Data Dementia Development Disease Disease Progression Disease model Evolution Exhibits Fractionation Functional disorder G3BP1 gene Gene Expression Gene Proteins Genes Genetic Genetic Polymorphism Genetic study Genomics Geography Goals Human Human Genetics Impaired cognition Inflammation Investigation Knowledge Label Laboratories Link MAPT gene Maps Mass Spectrum Analysis Mediating Methods Microglia Modeling Molecular Mus Nature Nerve Degeneration Neurofibrillary Tangles Neurons Outcome Pathologic Pathology Pattern Process Protein Dynamics Protein Isoforms Proteins Proteomics RNA-Binding Proteins Reproducibility Research Risk Factors Role Senile Plaques Structure Synapses Tauopathies Technology Testing Transcript Variant Work apolipoprotein E-3 apolipoprotein E-4 gene interaction genetic risk factor genomic data human data human genomics in vivo innovation insight invention knock-down macromolecule member neurofibrillary tangle formation neuronal cell body neuropathology overexpression prevent protein complex protein protein interaction protein structure response screening stress granule tau Proteins tau aggregation tau interaction tau mutation tool

项目摘要

The goal of this proposal is to determine how ApoE polymorphisms modify comprehensive maps and subnetworks of protein complexes that are central players in the dysfunction occurring Alzheimer’s disease (AD). We will use the emerging power of quantitative network proteomics in the Emili laboratory combined with proximity profiling to systematically characterize the major protein assemblies that occur in a classic disease model of tauopathy. This research will be propelled by discoveries from the Wolozin laboratory demonstrating that a dynamic network of protein interactions drives tau biology and changes with the course of disease. The work will be further informed by cross-referencing key network members to large genetics and genomics datasets focused on AD risk, neuropathological outcomes and human brain expression data to enable prioritization of network members exhibiting disease-linked gene-gene interactions. These advanced interactome screening technologies are uniquely suited for unbiased interrogations of disease-related protein networks in the brain. We hypothesize that tau and RNA binding protein interactomes exhibit a progressive evolution with disease progression in tauopathy, and that the structure of the interactomes is modified by genetic risk factors for AD. Aim 1 will determine how APOE alleles modify neuronal interactomes with disease progression. We will cross PS19 P301S tau mice with mice carrying humanized ApoE3 or ApoE4, and compare protein-protein interaction networks for tau and the RNA binding proteins TIA1 (which interacts with pathological tau) and G3BP (which does not interact with pathological tau). Aim 2 will determine how APOE alleles modify responses to propagated pathological tau. We will compare how propagation of different tau strains changes the proteins that interact with pathological tau, and how expression of specific ApoE isoforms modify the pattern of tau propagation and the nature of the resulting tau interactomes. Aim 3 will determine how reduction of key protein interactors modifies AD-related networks, and disease progression in tauopathy. This work will examine the how reducing key network components modifies related interactome networks and disease progression in PS19xApoE3 or E4 mice under conditions of normal disease progression or accelerated progression induced by tau propagation.

该提案的目标是确定Apoe多态性如何改变综合性蛋白质复合物的地图和子网络，这些蛋白质复合物是功能障碍的核心参与者，阿尔茨海默病（Alzheimer's Disease，AD）我们将利用量化网络的新兴力量 Emili实验室的蛋白质组学与邻近分析相结合，表征在tau蛋白病的经典疾病模型中发生的主要蛋白质组装。 Wolozin实验室的发现将推动这项研究，蛋白质相互作用的动态网络驱动着tau蛋白的生物学，病程。将通过交叉参考关键网络成员，大型遗传学和基因组学数据集，重点关注AD风险，神经病理学结果和人脑表达数据，以使得能够对表现出与疾病相关的基因间相互作用这些先进的相互作用体筛选技术是唯一适合于无偏询问疾病相关的蛋白质网络中，个脑袋我们假设tau蛋白和RNA结合蛋白相互作用组表现出进行性的在tau蛋白病中随着疾病进展的演变，并且相互作用体的结构是由AD的遗传风险因素改变。目的1将确定APOE等位基因如何修饰神经元相互作用体与疾病进展。我们将PS19 P301 S tau小鼠与小鼠杂交，携带人源化ApoE 3或ApoE 4，并比较蛋白-蛋白相互作用网络， tau蛋白和RNA结合蛋白TIA 1（与病理性tau蛋白相互作用）和G3 BP （其不与病理性tau相互作用）。目的2将确定APOE等位基因改变对传播的病理性tau的反应。我们将比较不同的tau蛋白株改变了与病理性tau蛋白相互作用的蛋白质，特异性ApoE同种型的表达改变了tau蛋白增殖的模式和产生的tau相互作用体。目标3将确定如何减少关键蛋白质相互作用物改变AD相关网络和tau蛋白病的疾病进展。这项工作将审查减少关键网络组件如何修改相关的交互式网络，正常疾病条件下PS19 xApoE 3或E4小鼠的疾病进展进展或加速进展。