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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

项目概要/摘要进行性核上性麻痹 (PSP) 和皮质基底节变性 (CBD) 是帕金森病尸检时主要的 tau 蛋白病理学。与微管相关的常见非重组单倍型染色体 17q21 上的 tau 蛋白基因 (MAPT) 位点会增加 PSP 和 CBD 的风险，最近我们发现全基因组关联工作发现了其他基因/基因座的变异（STX6、EIF2AK3、SOS1、KIF13B、和 MOBP/凋亡素）。此外，其他尚未被发现的基因可能会导致 PSP 易感性和CBD。本研究旨在解决外显子组和整体内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 病理学为特征的复杂神经退行性疾病的潜在机制，因此确定潜在的治疗靶点。对于目标 1，我们将分析一个包含 600 多个数据的独特数据集来自病理证实的 PSP 患者的外显子组和 2400 个全基因组序列以及 350 个外显子组来自 CBD 患者。这些数据将与通过阿尔茨海默病获得的 5000 个对照外显子组进行比较用于单核苷酸变异（SNV）分析的测序项目。在目标 2 中，我们将扩展对此的分析队列并专门分析有助于的结构变异（SV）和拷贝数变异（CNV） PSP 和 CBD 使用一系列分析软件程序，我们已经对其进行了广泛测试以实现每种类型变化的最佳灵敏度。对于目标 3，我们将使用可用的外显子组和全基因组序列数据来评估遗传变异对 tau 毒性和病理学与核心 C 的关联，通过评估不同大脑区域的 tau 蛋白负荷和小胶质细胞增生作为神经元细胞损失的替代指标。正在进行中研究表明，使用定量病理学测量可以帮助区分 PSP 的亚型。为了目标 4，我们将确定已识别的显着相关变体/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 蛋白水平和死后脑组织中的亚型。综上所述，全外显子组和全基因组的结合来自病理确诊和高表型患者的序列数据，并制定深入的分析计划专注于 SNV、CNV、SV 和数量性状，为新基因发现提供了独特的机会。识别 tau蛋白病的新基因是更好地理解 tau蛋白病的关键一步这组疾病的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的疾病。