Illuminating neurodegenerative tauopathy from somatic genomic landscapes of single human brain cells

从单个人脑细胞的体细胞基因组景观中阐明神经退行性 tau 病

• 批准号: 10686570
• 负责人: Michael B Miller
• 金额: $ 161.1万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10686570
• 关键词: Address; Affect; Age; Alzheimer' s Disease; American; Biological; Biological Models; Brain; Cause of Death; Cell Death; Cell Nucleus; Cell model; Cells; DNA; Dementia; Deposition; Diagnostic; Disease; Event; Family; Functional disorder; Genome; Genomics; Human; Individual; Methods; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neurons; Oxidative Stress; Population; Process; Research; Resources; Role; Signal Transduction; Single Nucleotide Polymorphism; Societies; Somatic Mutation; Sorting; System; Tauopathies; Technology; Testing; Therapeutic; Time; Work; brain cell; brain tissue; genome sequencing; genome-wide; human tissue; misfolded protein; novel sequencing technology; novel strategies; tau Proteins; tau aggregation; whole genome

PROJECT SUMMARY / ABSTRACT Neurodegenerative diseases, which include Alzheimer’s (AD), primary tauopathies, and other dementias, affect more than 6.5 million Americans with significant challenges for families and society. The hallmark of neurodegenerative disease is the stereotypical deposition of misfolded protein in the brain, with primary tauopathies showing tau accumulation in neurons and glia. The basis for cellular dysfunction in primary tauopathies is not well understood, underscoring an important need to broaden the biologic scope of research. Technological advances, based on single-cell whole-genome sequencing (scWGS) on human brain tissue, now allow examination of previously inaccessible aspects of the genome of individual cells in the brain. My colleagues and I have found that neurons in individuals with AD show greater somatic single-nucleotide variants (sSNV) in their genomes than in individuals without AD. From mutational signature analysis, specific causes of somatic mutations differed in AD, implicating oxidative stress and additional signal suggesting other cytopathologic events. This study will assess somatic mutation in the setting of primary tauopathies, based on four complementary themes. I will examine the process of genome-wide somatic mutation in neurons and glia in brain from individuals with primary tauopathy, and in a cellular model system we can dissect specific contributors to mutational mechanisms. I will also use single-cell functional studies to probe mechanisms of cell death in primary tauopathy. Throughout the study, I will use new single-cell cytopathological methods to study the role of tau in somatic mutation and broader disease mechanisms. With complementary approaches of novel scWGS technology, single-nucleus sorting, and unique human tissue and cellular system resources, I will examine the mechanistic role of somatic mutations in primary tauopathy. This work stands to address fundamental questions in neurodegeneration and develop new approaches for identification of disease mechanisms, with the potential for broad application for better diagnostic and therapeutic options.

项目摘要 /摘要 神经退行性疾病，包括阿尔茨海默氏症（AD），原发性tauopathies和其他痴呆症， 影响超过650万美国人对家庭和社会面临重大挑战的美国人。标志的标志 神经退行性疾病是大脑中错误折叠蛋白的刻板印象，主要折叠蛋白 Tauopathies显示Tau在神经元和神经胶质中的积累。原发性细胞功能障碍的基础 陶氏病尚不清楚，强调了扩大生物学研究范围的重要需求。 技术进步，基于人脑组织的单细胞全基因组测序（SCWG） 现在允许检查大脑中单个细胞基因组以前无法访问的方面。我的 我和同事发现AD患者的神经元显示出更大的体细胞单核苷酸 其基因组中的变体（SSNV）比没有AD的个体中的变体（SSNV）。根据突变签名分析，特定 AD中的体细胞突变的原因，隐式氧化应激和其他信号表明其他信号 细胞病理事件。 这项研究将基于四个完整性的原发性tauopathies的躯体突变评估躯体突变 主题。我将检查神经元中全基因组躯体突变的过程 患有原发性扭曲的个体，在细胞模型系统中，我们可以将特定贡献者剖析 突变机制。我还将使用单细胞功能研究来探测细胞死亡的机制 原发性tauopathy。在整个研究中，我将使用新的单细胞细胞病理学方法来研究角色 tau在体细胞突变和更广泛的疾病机制中的作用。采用新颖的方法 SCWGS技术，单核分类以及独特的人体组织和细胞系统资源，我将 检查体突变在原发性tauopathy中的机械作用。这项工作将解决 神经变性中的基本问题，并开发了鉴定疾病的新方法 机制，有可能广泛应用更好的诊断和治疗选择。