Project 1: Identifying genes and Pathways that impact Tau Toxicity in FTD

项目 1：识别影响 FTD 中 Tau 毒性的基因和途径

• 批准号: 10012956
• 负责人: GERARD DAVID SCHELLENBERG
• 金额: $ 45.94万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10012956
• 关键词: 17q21; Affect; Agreement; Alzheimer' s Disease; Architecture; Autopsy; Biological; Biological Assay; Biological Models; Brain; Brain region; Candidate Disease Gene; Cerebellum; Chromosome Mapping; Chromosomes; Clinic; Cohort Analysis; Complement; Complex; Computer software; Copy Number Polymorphism; Data; Data Set; Disease; Etiology; Expression Profiling; Funding; Future; Gene Expression; Gene Expression Regulation; Gene-Modified; Genes; Genetic; Genetic Variation; Genotype; Grant; Haplotypes; Human Resources; In Vitro; Logistic Regressions; MAPT gene; Measures; Messenger RNA; Microtubules; Modeling; Mus; Mutation; National Heart, Lung, and Blood Institute; National Human Genome Research Institute; Neurodegenerative Disorders; Occipital lobe; Parkinsonian Disorders; Pathologic; Pathology; Pathway Analysis; Pathway interactions; Patients; Phenotype; Plasma; Predisposition; Prognostic Marker; Progressive Supranuclear Palsy; Protein Isoforms; Regression Analysis; Risk; Role; Sampling; Single Nucleotide Polymorphism; Structure; Tauopathies; Testing; Tissues; Toxic effect; Trans-Omics for Precision Medicine; Transcript; United States National Institutes of Health; Variant; Work; base; biobank; brain tissue; caudate nucleus; corticobasal degeneration; exome; gene discovery; genetic association; genetic variant; genome wide association study; genome-wide; genomic locus; in vitro Model; in vivo; induced pluripotent stem cell; mRNA Expression; neuron loss; next generation sequencing; novel; potential biomarker; programs; protein expression; risk variant; structural genomics; tau Proteins; tau aggregation; therapeutic target; tool; trait; transcriptome sequencing; whole genome

PROJECT SUMMARY/ABSTRACT Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are Parkinsonian disorders with predominant tau pathology at autopsy. A common non-recombining haplotype at the microtubule associated protein tau gene (MAPT) locus on chromosome 17q21 increases the risk of PSP and CBD and recently our genome-wide association efforts identified variation in additional genes/loci (STX6, EIF2AK3, SOS1, KIF13B, and MOBP/Appoptosin). In addition, other genes, as yet undetected, likely contribute to susceptibility to PSP and CBD. This study aims to resolve the disease-associated genetic variation within the exome and whole genome sequence data from PSP and CBD patients, to determine the pathological consequences and mechanisms underlying these complex neurodegenerative diseases characterized by tau pathology, thus identifying potential therapeutic targets. For Aim 1, we will analyze a unique dataset consisting of over 600 exomes and 2400 whole genome sequences derived from pathology-confirmed PSP patients and 350 exomes from CBD patients. These data will be compared to the 5000 control exomes available through the Alzheimer's sequencing project for single nucleotide variant (SNV) analysis. In Aim 2, we will expand our analysis of this cohort and specifically analyze structural variants (SV) and copy number variations (CNV) that contribute to PSP and CBD using a range of analytical software programs which we have extensively tested to achieve optimal sensitivity for each type of variation. For Aim 3, we will use the available exome and whole genome sequence data to assess the association of genetic variation on tau toxicity and pathology with Core C, by assessing tau burden in different brain regions and microgliosis as a surrogate of neuronal cell loss. On-going efforts have shown that using quantitative pathologic measures can help distinguish subtypes of PSP. For Aim 4, we will determine the effect of significantly associated variants/genes identified. We will examine mRNA expression, RNA-Seq data, in vitro functional studies to characterize the effect of the observed mutation on tau aggregation and microtubule assembly, and the effect of these genes/variants on tau protein levels and isoforms in postmortem brain tissue. In summary, the combination of whole exome and whole genome sequence data from pathologically-confirmed and highly-phenotyped patients with an in-depth analytical plan focusing on SNV, CNV, SV and quantitative traits, provides a unique opportunity for novel gene discovery. Identifying novel genes for tauopathies is a critical step towards a better understanding of the pathomechanisms underlying this group of disorders and may help identify prognostic biomarkers for these devastating disorders.

项目摘要/摘要 进行性核上麻痹（PSP）和皮质型变性（CBD）是帕金森氏症患者 尸检时主要的tau病理学。与微管相关的常见非重组单倍型 染色体17q21上的蛋白质tau基因（MAPT）基因座增加了PSP和CBD的风险，最近我们 全基因组关联工作确定了其他基因/基因座的变化（STX6，EIF2AK3，SOS1，KIF13B， 和mobp/appoptosin）。此外，尚未发现的其他基因可能有助于PSP的敏感性 和CBD。这项研究旨在解决外显子和整个中与疾病相关的遗传变异 来自PSP和CBD患者的基因组序列数据，以确定病理后果和 这些以tau病理为特征的这些复杂的神经退行性疾病的机制，因此 确定潜在的治疗靶标。对于AIM 1，我们将分析一个由600多个超过600的唯一数据集 来自病理证实的PSP患者和350个外来的外体和2400个全基因组序列 来自CBD患者。这些数据将与通过阿尔茨海默氏症可用的5000个控制外组组进行比较 单核苷酸变体（SNV）分析的测序项目。在AIM 2中，我们将扩大对此的分析 队列，专门分析结构变体（SV）和拷贝数变化（CNV），这些变化有助于 PSP和CBD使用一系列分析软件程序，我们已经进行了广泛测试以实现 每种类型变化的最佳灵敏度。对于AIM 3，我们将使用可用的外部和整个基因组 序列数据评估TAU毒性和病理与核心C的遗传变异的关联， 评估不同大脑区域的tau负担和小胶质细胞症作为神经元细胞丧失的替代物。正在进行 努力表明，使用定量病理测量可以帮助区分PSP的亚型。目的 4，我们将确定已鉴定出的显着相关变体/基因的影响。我们将检查mRNA 表达，RNA-seq数据，体外功能研究，以表征观察到的突变对TAU的影响 聚集和微管组装，以及这些基因/变体对tau蛋白水平和 验尸后脑组织中的同工型。总而言之，整个外显子组和整个基因组的结合 来自具有深入分析计划的病理确认和高度典型的患者的序列数据 专注于SNV，CNV，SV和定量特征，为新颖的基因发现提供了独特的机会。 识别扭曲的新基因是朝着更好地理解的关键一步 这组疾病的基础病理机制，可能有助于确定这些疾病的预后生物标志物 毁灭性疾病。