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

• 批准号: 10402076
• 负责人: DENNIS WILLIAM DICKSON
• 金额: $ 78.04万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 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/10402076
• 关键词: ATAC-seq; Affect; Alzheimer' s disease related dementia; Award; Biological Assay; Cell Line; Cells; Code; Collection; Data; Deposition; Disease; Epigenetic Process; Equilibrium; Female; Gene Expression Profiling; Genetic; Genomics; Goals; Harvest; Lobar; MAPT gene; Mutation; National Institute of Neurological Disorders and Stroke; Nerve Degeneration; Parents; Pathologic; Pathway interactions; Patients; Phenotype; Predisposition; Production; Progressive Supranuclear Palsy; Quality Control; Research; Resources; Risk Factors; Standardization; Tauopathies; Untranslated RNA; Validation; Variant; genetic risk factor; genetic variant; genome sequencing; genome wide methylation; induced pluripotent stem cell; male; molecular phenotype; multiple omics; novel; parent grant; tau Proteins; tau mutation; whole genome

Abstract A broad range of neurodegenerative conditions, including AD and many ADRDs, such as PSP, FTLD are collectively known as “tauopathies” because the tau protein is a core feature of these diseases. Further, the MAPT locus is a major genetic risk factor for Frontemporal lobar degeneration (FTLD) spectrum disorders, including Progressive Supranuclear Palsy (PSP). Our parent grant involves extensive genomic analyses in PSP to identify new causal risk factors and understand their genetic mechanisms. Here, we propose a supplement leveraging many of the same approaches used in the parent grant to comprehensively perform genetic and genomic characterization of a collection of 100 Induced Pluripotent Stem Cell (IPSC) lines with mutations in the microtubule-associated protein tau (MAPT) and controls. By including a balance of male and female lines, multiple lines for most of the major mutations, and including isogenic and uncorrected controls, we will provide an unprecedented resource for ADRD research. We will culture and harvest all patient and edited isogenic IPSC lines under rigorously standardized, highly controlled conditions for downstream genetic and genomic analyses. We will use a multi-omics approach involving whole genome sequencing, bulk and single cell transcriptional profiling and epigenetic assays, including genome wide methylation and single cell ATAC-seq. By providing deep quality control and molecular phenotyping in this unique set of IPSC lines, the data production supported by this supplement will define the quality and integrity of the lines and enable the study of the mechanism (s) by which genetic variants influence convergent ADRD pathways. These lines will be deposited at NHCDR, and the deep genomic and epigenetic phenotyping and genetic data will be made publicly available in a coordination with NINDS staff.

抽象的 多种神经退行性疾病，包括 AD 和许多 ADRD，例如 PSP、FTLD 统称为“tau蛋白病”，因为 tau 蛋白是这些疾病的核心特征。 MAPT 位点是额颞叶变性 (FTLD) 谱系疾病的主要遗传风险因素， 包括进行性核上性麻痹 (PSP) 我们的家长资助涉及 PSP 的广泛基因组分析。 为了识别新的因果风险因素并了解其遗传机制，我们在这里提出了补充。 利用许多与父母资助中使用的相同方法来全面执行遗传和 对 100 个具有突变的诱导多能干细胞 (IPSC) 系进行基因组表征 微管相关蛋白 tau (MAPT) 和对照通过平衡雄性和雌性系， 大多数主要突变的多系，包括同基因和未校正的对照，我们将提供 我们将培养和收获所有患者和编辑的同基因 IPSC。 在严格标准化、高度控制的条件下生产线，用于下游遗传和基因组分析。 我们将使用多组学方法，涉及全基因组测序、批量和单细胞转录 分析和表观遗传学分析，包括全基因组甲基化和单细胞 ATAC-seq。 在这套独特的IPSC线中进行质量控制和分子表型分析，由此支持的数据生产 补充品将定义品系的质量和完整性，并能够研究其机制 遗传影响变异会聚 ADRD 途径，这些细胞系将被存放在 NHCDR 和深部。 基因组和表观遗传表型以及遗传数据将与以下机构协调公开： 国家统计局工作人员。

项目成果

Cellular and pathological heterogeneity of primary tauopathies.

原发性 tau 蛋白病的细胞和病理异质性。

• 发表时间: 2021-08-23
• 影响因子: 15.1
• 作者: Chung, Dah;Roemer, Shanu;Petrucelli, Leonard;Dickson, Dennis W
• 通讯作者: Dickson, Dennis W

Identification and characterization of constrained non-exonic bases lacking predictive epigenomic and transcription factor binding annotations.

缺乏预测表观基因组和转录因子结合注释的受限非外显子碱基的鉴定和表征。

• 发表时间: 2020
• 影响因子: 16.6
• 作者: Grujic, Olivera;Phung, Tanya N;Kwon, Soo Bin;Arneson, Adriana;Lee, Yuju;Lohmueller, Kirk E;Ernst, Jason
• 通讯作者: Ernst, Jason

Associations of mitochondrial genomic variation with corticobasal degeneration, progressive supranuclear palsy, and neuropathological tau measures.

线粒体基因组变异与皮质基底节变性、进行性核上性麻痹和神经病理学 tau 蛋白测量的关联。

• 发表时间: 2020-09-17
• 影响因子: 7.1
• 作者: Valentino, Rebecca R;Tamvaka, Nikoleta;Heckman, Michael G;Johnson, Patrick W;Soto;Walton, Ronald L;Koga, Shunsuke;Uitti, Ryan J;Wszolek, Zbigniew K;Dickson, Dennis W;Ross, Owen A
• 通讯作者: Ross, Owen A

Latent trait modeling of tau neuropathology in progressive supranuclear palsy.

进行性核上性麻痹中 tau 神经病理学的潜在特征模型。

• 发表时间: 2021-05
• 影响因子: 12.7
• 作者: Kouri, Naomi;Murray, Melissa E;Reddy, Joseph S;Serie, Daniel J;Soto;Allen, Mariet;Carrasquillo, Minerva M;Wang, Xue;Castanedes, Monica Casey;Baker, Matthew C;Rademakers, Rosa;Uitti, Ryan J;Graff;Wszolek, Zb
• 通讯作者: Wszolek, Zb

Functional regulatory variants implicate distinct transcriptional networks in dementia.

功能调节变异涉及痴呆症中不同的转录网络。

• 发表时间: 2022-08-19
• 作者: Cooper, Yonatan A;Teyssier, Noam;Dräger, Nina M;Guo, Qiuyu;Davis, Jessica E;Sattler, Sydney M;Yang, Zhongan;Patel, Abdulsamie;Wu, Sarah;Kosuri, Sriram;Coppola, Giovanni;Kampmann, Martin;Geschwind, Daniel H
• 通讯作者: Geschwind, Daniel H