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.

进行性核上性麻痹 (PSP) 是与 tau 病理学相关的最常见的额颞叶变性，虽然在 PSP 中发现了罕见的致病变异、常见的危险因素，以及最近发现的罕见的风险相关变异，但其遗传性占很大比例。神经退行性tau蛋白病和其他额颞叶变性仍然无法解释，这表明还有其他遗传风险因素等待发现。在本申请中，我们建议鉴定相关的新遗传变异。首先，我们将通过神经病理学特征的 PSP 的全基因组测序来检测变异；其次，我们将通过递归分析对病理脑组织样本进行多维筛选，包括转录、蛋白质组学和表观遗传学分析。最后，我们将使用高通量功能筛选来跟踪这些变异，该项目利用了前所未有的病理资源。 PSP 的研究，利用在私人基金会的支持下创建的病理和遗传基础设施，并提供改变我们对 PSP 遗传结构的理解，并推进这种典型 tau 蛋白病的生物学和下游效应。

项目成果

期刊论文数量（19）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Distribution and characteristics of transactive response DNA binding protein 43 kDa pathology in progressive supranuclear palsy.

进行性核上性麻痹中交互反应 DNA 结合蛋白 43 kDa 病理学的分布和特征。

DOI：
发表时间：
2017-02
期刊：
影响因子：
0
作者：
Koga, Shunsuke;Sanchez;Josephs, Keith A;Uitti, Ryan J;Graff;van Gerpen, Jay A;Cheshire, William P;Wszolek, Zbigniew K;Rademakers, Rosa;Dickson, Dennis W
通讯作者：
Dickson, Dennis W

Comments on an autopsy case of progressive supranuclear palsy treated with monoclonal antibody against tau.

对用 tau 单克隆抗体治疗的进行性核上性麻痹尸检病例的评论。

DOI：
发表时间：
2023-12
期刊：
影响因子：
0
作者：
Koga, Shunsuke;Dickson, Dennis W;Wszolek, Zbigniew K
通讯作者：
Wszolek, Zbigniew K

Cerebrovascular pathology and misdiagnosis of multiple system atrophy: An autopsy study.

脑血管病理学和多系统萎缩的误诊：尸检研究。

DOI：
10.1016/j.parkreldis.2020.05.018
发表时间：
2020-06
期刊：
Parkinsonism & related disorders
影响因子：
4.1
作者：
Koga, Shunsuke;Roemer, Shanu F.;Tipton, Philip W.;Low, Phillip A.;Josephs, Keith A.;Dickson, Dennis W.
通讯作者：
Dickson, Dennis W.

Retrospective Evaluation of Neuropathologic Proxies of the Minimal Atrophy Subtype Compared With Corticolimbic Alzheimer Disease Subtypes.

与皮质边缘阿尔茨海默病亚型相比，最小萎缩亚型的神经病理学指标的回顾性评估。

DOI：
发表时间：
2023-10-03
期刊：
影响因子：
9.9
作者：
Boon, Baayla D C;Labuzan, Sydney A;Peng, Zhongwei;Matchett, Billie J;Kouri, Naomi;Hinkle, Kelly M;Lachner, Christian;Ross, Owen A;Ertekin;Carter, Rickey E;Ferman, Tanis J;Duara, Ranjan;Dickson, Dennis W;Graff
通讯作者：
Graff

Human Molecular Genetics Review Issue 2022.

人类分子遗传学评论 2022 年。