New Down syndrome brain organization revealed by single-cell genomics

单细胞基因组学揭示了新的唐氏综合症大脑组织

• 批准号: 10471627
• 负责人: JEROLD CHUN
• 金额: $ 139.53万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10471627
• 关键词: Acute; Address; Adult; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease pathology; Amyloid beta-Protein Precursor; Antibodies; Biological; Biological Markers; Biomedical Engineering; Brain; Brain Diseases; CAR T cell therapy; Cause of Death; Cell Nucleus; Cells; Child; Chromatin; Chromosome 21; Clinical; Clinical Trials; Cognition; Communities; DNA; DNA Sequence; DNA Sequence Alteration; Data; Dementia; Detection; Deterioration; Diagnosis; Disease; Down Syndrome; Elements; Environment; Enzymatic Biochemistry; Epilepsy; Etiology; FDA approved; Future; Gene Dosage; Gene Expression; Genes; Genetic Recombination; Genetic Transcription; Genome; Genomic DNA; Genomics; Heterogeneity; Human; Human Chromosomes; Immune system; Individual; Informatics; Knowledge; Lead; Learning; Life; Literature; Longevity; Malignant Neoplasms; Medicine; Memory; Molecular; Mosaicism; Neurobiology; Neuroglia; Neurologist; Neurons; Nucleotides; Onset of illness; Pathogenesis; Pathogenicity; Protein Isoforms; Quality of life; RNA-Directed DNA Polymerase; Reporting; Research; Reverse Transcriptase Inhibitors; Role; Site; Somatic Cell; Symptoms; Technology; Testing; Therapeutic; Time; Trisomy; V(D)J Recombination; Variant; age related; aged; autism spectrum disorder; base; brain cell; brain dysfunction; cell type; comorbidity; deficit syndrome; early onset; efficacious treatment; familial Alzheimer disease; gene product; human disease; improved; induced pluripotent stem cell; innovation; neuropathology; novel; novel therapeutics; operation; prevent; stem cell model; transcriptome; transcriptomics

PROJECT SUMMARY/ABSTRACT Nearly 100% of Down syndrome (DS; trisomy of human chromosome 21) individuals that live into their 5th decade of life and beyond, show Alzheimer’s disease (AD)-like dementia and neuropathology (DS-AD), representing a prominent DS comorbidity that has recently been reported as the leading cause of death for DS adults. Beyond trisomy of chromosome 21, which includes the key AD gene, amyloid precursor protein (APP), the molecular mechanisms underlying DS-AD have resisted identification. There are no disease-modifying therapies (DMTs) to prevent or treat DS-AD, which could improve DS quality of life and lifespan. This INCLUDE proposal will transform our understanding of DS by revealing the transcriptomic (RNA) and genomic (DNA) single-cell landscape of the aging DS individual, and especially the DS-AD brain, by centering upon a novel human brain molecular mechanism that might underlie DS-AD: somatic gene recombination (SGR) and resultant genomic and transcriptomic heterogeneity. SGR has the potential to change the DNA blueprint of DS brain cells resulting in functional consequences for brain cells that could explain DS-AD onset as well as other DS brain comorbidities such as autism and epilepsy. SGR has not been examined in DS brains, which if operational, would provide a fundamentally new view on how genes and gene dosage act to promote DS-AD over time. SGR is known to act on APP in normal and sporadic AD neurons, resulting in thousands of new APP variants within individual human brains and has been independently confirmed in the scientific literature. The proven increases in DS brain gene expression, combined with the identified linkage of gene expression to SGR, implicates genes transcriptionally increased by trisomy 21 as new targets for SGR in DS-AD. APP is likely the “tip of the iceberg” for DS-affected genes in neurons and non-neuronal cells, with implications for both DS as well as other states of the normal and diseased human brain. Three independent, but deeply-connected, Research Elements (REs) will be completed by a proven, collaborative team of molecular biologists, neuroscientists, neurologists, bioengineers, and bioinformaticians to test the hypothesis that SGR contributes to DS brain deficits and DS-AD by altering known and unknown disease genes at the single-cell transcriptomic and genomic level within the DS brain. RE1 and RE2 will use cutting-edge sequencing technologies to interrogate the transcriptomic and genomic heterogeneity of single nuclei from DS and DS-AD brains compared to controls, and will informatically integrate transcriptomic expression, chromatin accessibility, novel isoform detection and genomic mosaicism forms, including gencDNAs, within single cells across cell types and with age. RE3 will explore the functional consequences SGR in primary neuronal and induced pluripotent stem cell (iPSC) models towards understanding the functional implications of disease enhanced SGR, and the therapeutic opportunities that SGR unveils.

项目概要/摘要 近 100% 的唐氏综合症（DS；人类 21 号染色体三体）个体都能活到 50 岁 生命及其他方面，显示了类似阿尔茨海默氏病 (AD) 的痴呆和神经病理学 (DS-AD)，代表了 最近被报道为 DS 成人死亡的主要原因。 21 号染色体三体，包括关键的 AD 基因、淀粉样前体蛋白 (APP)、分子 DS-AD 的潜在机制尚未被识别。目前尚无疾病缓解疗法 (DMT)。 预防或治疗 DS-AD，从而提高 DS 的生活质量和寿命。 该 INCLUDE 提案将通过揭示转录组 (RNA) 和 衰老 DS 个体，尤其是 DS-AD 大脑的基因组（DNA）单细胞景观，通过集中 基于可能是 DS-AD 基础的一种新型人脑分子机制：体细胞基因重组 (SGR) 由此产生的基因组和转录组异质性有可能改变 DNA 蓝图。 DS 脑细胞对脑细胞产生功能性影响，这可以解释 DS-AD 的发病以及 其他 DS 大脑合并症，例如自闭症和癫痫症，尚未在 DS 大脑中进行检查。 操作，将为基因和基因剂量如何促进 DS-AD 提供一个全新的观点 随着时间的推移，SGR 会作用于正常和偶发性 AD 神经元中的 APP，从而产生数千个新的 APP。 人类大脑内部存在变异，并已在科学文献中得到独立证实。 已证实 DS 脑基因表达增加，结合已确定的基因表达与 SGR 的联系， 暗示 21 三体性转录增加的基因可能是 DS-AD 中 SGR 的新靶标。 神经元和非神经元细胞中受 DS 影响的基因的“冰山一角”，对 DS 和非神经元细胞的影响 以及正常和患病人类大脑的三种独立但紧密相连的状态。 研究要素（RE）将由经过验证的分子生物学家协作团队完成， 神经科学家、神经学家、生物工程师和生物信息学家测试 SGR 贡献的假设 通过改变单细胞已知和未知的疾病基因来治疗 DS 脑缺陷和 DS-AD DS 大脑内的转录组和基因组水平将使用尖端测序。 探究 DS 和 DS-AD 单核转录组和基因组异质性的技术 大脑与对照组进行比较，并将以信息方式整合转录组表达、染色质可及性、 跨细胞类型的单细胞内新的亚型检测和基因组嵌合形式，包括 gencDNA 随着年龄的增长，RE3 将探索 SGR 对初级神经和诱导多能的功能影响。 干细胞（iPSC）模型旨在了解疾病增强的 SGR 的功能影响，以及 SGR 揭示的治疗机会。