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.

项目总结/文摘