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：
10386807
负责人：
Andrew EMILI
金额：
$ 64.95万
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 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10386807
关键词：
Address Affect Alleles Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease risk Amyloid beta-Protein Apolipoprotein E Automobile Driving Biochemical Biology Biotinylation Brain 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 Isoforms Proteins Proteomics RNA-Binding Proteins Research Risk Factors Role Senile Plaques Structure Synapses Tauopathies Technology Testing Transcript Variant Work apolipoprotein E-3 apolipoprotein E-4 base gene interaction genetic risk factor genetic testing genomic data human data human genomics in vivo innovation insight invention knock-down macromolecule member neurofibrillary tangle formation neuronal cell body overexpression prevent protein complex protein protein interaction protein structure response screening stress granule tau Proteins tau aggregation tau expression 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.

该提案的目的是确定APOE多态性如何修改全面蛋白质复合物的地图和子网，它们是功能障碍中核心参与者发生阿尔茨海默氏病（AD）。我们将使用定量网络的新兴力量 Emili实验室中的蛋白质组学结合了与系统的近端分析表征了经典的tauopathy疾病模型中发生的主要蛋白质组件。这项研究将由Wolozin实验室的发现推动，证明蛋白质相互作用的动态网络推动了tau生物学，并随着病程。通过交叉引用关键网络成员将进一步告知这项工作大型遗传学和基因组学数据集侧重于AD风险，神经病理学结果和人脑表达数据以实现表现出的网络成员的优先级疾病连接的基因 - 基因相互作用。这些高级互动筛选技术独特地适合于对疾病相关蛋白网络的公正询问脑。我们假设tau和RNA结合蛋白相互作用暴露了进行性呼吸疾病中疾病进展的进化，相互作用的结构是通过AD的遗传危险因素修饰。 AIM 1将确定APOE等位基因如何修改神经元与疾病进展的相互作用。我们将用小鼠穿越PS19 P301S Tau小鼠携带人性化的APOE3或APOE4，并比较蛋白质 - 蛋白质相互作用网络的 tau和RNA结合蛋白TIA1（与病理TAU相互作用）和G3BP （这不与病理tau相互作用）。 AIM 2将决定APOE等位基因修改对传播病理tau的反应。我们将比较如何传播不同的tau菌株会改变与病理tau相互作用的蛋白质，以及如何特定APOE同工型的表达修改了Tau传播的模式和性质由此产生的tau相互作用。 AIM 3将确定关键蛋白质相互作用者的减少修饰与广告相关的网络和tauopathy中的疾病进展。这项工作将检查减少密钥网络组件的方式修改了相关的Interactome网络和在正常疾病的情况下，PS19XAPOE3或E4小鼠的疾病进展 tau传播引起的进展或加速进展。