Impact of coding and non-coding variation in progressive supranuclear palsy

编码和非编码变异对进行性核上性麻痹的影响

基本信息

批准号：
10252910
负责人：
DENNIS WILLIAM DICKSON
金额：
$ 88.39万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-25 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10252910
关键词：
17q21 ATAC-seq Affect Agreement Algorithms Biological Assay Biology Brain Characteristics Clinic Clinical Cloud Computing Code Collaborations Collection Complex Data Data Analyses Disease Disease susceptibility Epigenetic Process Foundations Frontotemporal Dementia Frontotemporal Lobar Degenerations Gene Expression Regulation Genetic Genetic Determinism Genetic Transcription Genetic Variation Genome Genomic Segment Genomics Goals Heritability Infrastructure Knowledge Methods Nerve Degeneration Neurons Occipital lobe Parkinson Disease Pathogenicity Pathologic Pathology Patients Phase Phenotype Play Predisposition Privatization Process Progressive Nonfluent Aphasias Progressive Supranuclear Palsy Proteomics Resources Risk Factors Role Sampling Severities Single Nucleotide Polymorphism Site Structure Syndrome Tauopathies Thalamic structure Tissue Sample Untranslated RNA Validation Variant accurate diagnosis base bioinformatics pipeline brain tissue corticobasal syndrome disorder risk follow-up genetic architecture genetic risk factor genetic variant genome sequencing high throughput screening member neuron loss novel risk variant tau Proteins transcriptome sequencing transcriptomics whole genome

项目摘要

Progressive supranuclear palsy (PSP) is the most common frontotemporal lobar degeneration associated with tau pathology. While rare pathogenic variants, common risk factors, and – more recently – rare risk-associated variants have been identified in PSP, a significant proportion of the heritability for neurodegenerative tauopathies and other frontotemporal lobar degenerations remains unexplained, strongly suggesting that additional genetic risk factors await discovery. In this application, we propose to identify novel genetic variation associated with PSP using a multi-stage strategy. First, we will detect variants through whole-genome sequencing of neuropathologically characterized PSP. Second, we will prioritize pathological brain tissue samples for a multidimensional screen that includes transcriptional, proteomics, and epigenetic assays. Through recursive application of a prioritization algorithm, regions and variants most likely to have a high impact on disease risk will be identified. Finally, we will follow up on these variants using a high-throughput functional screen. This project taps unprecedented pathologic resources of PSP, leverages a pathologic and genetic infrastructure created with support from private foundations, and offers to transform our understanding of the genetic architecture of PSP and to advance towards the biology and downstream effects of this prototypical tauopathy downstream effects of this prototypical tauopathy.

进行性上腹部麻痹（PSP）是与Tau病理学相关的最常见的额颞叶变性。尽管在PSP中已经确定了罕见的致病性变异，常见的危险因素和（最近）罕见的风险相关变体，但神经退行性tauopathies的遗传力中很大一部分和其他额颞叶退化仍然无法解释，这强烈暗示了其他遗传危险因素等待发现。我们建议使用多阶段策略确定与PSP相关的新遗传变异。首先，我们将通过神经病理学表征的PSP的全基因组测序来检测变体。其次，我们将优先考虑包括转录，蛋白质组学和表观遗传方法的多维屏幕的病理脑组织样品。通过递归应用优先级算法，将确定最大的区域和变体对疾病风险产生很大的影响。最后，我们将使用高通量功能屏幕对这些变体进行跟进。该项目利用了PSP的前所未有的病理资源，利用了一种在私人基金会的支持下创建的病理和遗传基础设施，并提供了我们对PSP遗传结构的理解，并迈向了这种原型to型Tauopathy this Prototypical Taupatial taupathy的生物学和下游效应。