A mosaic Down syndrome model system comparing isogenic trisomic/disomic cells to unmask trisomy-21 related genomic, epigenomic, and senescence changes acquired across the lifespan

镶嵌唐氏综合症模型系统比较同基因三体/二体细胞，以揭示在整个生命周期中获得的与 21 三体相关的基因组、表观基因组和衰老变化

• 批准号: 10656746
• 负责人: COLLEEN K JACKSON-COOK
• 金额: $ 221.74万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10656746
• 关键词: 21 year old; Acceleration; Adolescence; Adult; Age; Aging; Algorithms; Aneuploidy; Area; Behavioral; Bioinformatics; Biological; Biological Assay; Biological Factors; Biological Markers; Biological Models; Blood; Bystander Effect; Cataract; Cells; Childhood; Chromosome 21; Chromosomes; Clinical Research; Cytogenetics; Cytoplasm; DNA; DNA Methylation; Data; Dementia; Development; Disease; Down Syndrome; Early Onset Alzheimer Disease; Epigenetic Process; Event; Fluorescent in Situ Hybridization; Frequencies; Functional disorder; Gene Expression; General Population; Genomics; Goals; Health; Homeostasis; Immunofluorescence Immunologic; Immunologic Surveillance; Individual; Inflammation; Interferons; Knowledge; Lead; Length; Longevity; Longitudinal Studies; Lymphocyte; Measures; Mediating; Mediator; Methods; Methylation; Micronucleus Tests; Modeling; Mosaicism; Natural Immunity; Outcome; Pathway interactions; Pattern; Personal Satisfaction; Persons; Phenotype; Physicians; Process; Quality of life; Research; Research Design; Risk; Role; Sentinel; Somatic Cell; Specimen; Spectral Karyotyping; Stimulator of Interferon Genes; Symptoms; System; Technology; Telomere Shortening; Testing; Therapeutic; Time; Tissues; age related; beta-Galactosidase; cell type; cytokine; early detection biomarkers; emerging adult; epigenomics; expectation; follow-up; genetic makeup; genome-wide; genome-wide analysis; hearing impairment; improved; infancy; methylation pattern; micronucleus; mortality; mosaic; new therapeutic target; novel; phenotypic data; proband; reduce symptoms; response; screening; senescence; telomere; timeline; tool; trait; transcriptome; transcriptomics

PROJECT SUMMARY Down syndrome (Ds) has been associated with multiple, co-occurring health and behavioral conditions, as well as precocious (or accelerated) aging. The results of recent clinical studies are providing a clearer picture of health outcomes in childhood, adolescence, and early adulthood in people with Ds; yet very little is known about the cascade of trisomy 21-related biological changes that arise to culminate in the development of co-occurring conditions. The recent discovery of cytosolic DNA as an “integrator” of changes acquired in somatic cells provides a new research direction for identifying age- and trisomy 21-related biological alterations. Cells can acquire cytosolic DNA via micronuclei (MN) formation and extrachromosomal telomere circles (t-circles). A subset of this cytoplasmic self-DNA is recognized by innate immune surveillance pathways, which, in turn, lead to increased levels of senescence. We hypothesize that trisomy 21 increases MN levels and telomere attrition, leading to a perpetuating cycle of senescence and methylation alterations that accumulate/increase in frequency with age. One powerful approach for discovering trisomy 21-specific alterations is to evaluate biological attributes in cells from people with mosaicism for trisomy 21 (mDs). One can unmask and quantify trisomy 21-induced changes by “subtracting” values observed in isogenic disomic cells from those present in trisomic cells (thereby removing the confounding effects due to total background genetic make-up, as well as environmental influences). Thus, to identify the impact of a trisomy 21 imbalance on cytosolic DNA pathways, we will longitudinally compare biological measures in isogenic trisomic versus disomic cells from 65 people with mDs over 3 time points, (including baseline data, and spanning as much as 30 years of follow-up). To test our study hypothesis, we will quantify: (1) cytosolic self-DNA via a MN assay; (2) subtelomere/telomere alterations or dysfunction; (3) senescence patterns and cytokine levels; and (4) DNA methylation patterns. Each of these biological factors will be analyzed with “state of the art” tools we developed/optimized, which include: chromosome-specific assays for MN [SKY/FISH MN assay]); novel telomere/subtelomere length assays [Q-FISH & nanomapping]; telomere dysfunction assays; senescence, transcriptome, and cytokine marker assays; genome-wide studies for DNA methylation; and bioinformatic modeling. We will also collect/evaluate deep phenotype data. By interrogating relationships among and between biological measures with phenotypic traits, we will discover their role in mediating health outcomes. In summary, this longitudinal study of isogenic trisomic/disomic cells will enable us to “unmask” trisomy 21-associated changes in biological cascades and will provide the first assessment of the role of cytosolic DNA in health conditions associated with Ds/mDs. By identifying driver/mediator relationships between biomarkers, we will create new algorithms that will help physicians recognize health conditions at an earlier age in people with Ds/mDs. Importantly, we will identify new therapeutic targets that could transform our approach for developing treatments to alleviate symptoms of health conditions acquired by people with mDs/Ds.

项目摘要 唐氏综合症（DS）也与多个同时发生的健康和行为条件有关 早熟（或加速）衰老。最近的临床研究结果提供了更清晰的了解 DS患者的童年，青少年和成年早期的健康成果；但对 在同时发生的发展中，出现的一系列三体级三体性生物学变化 状况。最近发现的胞质DNA是在体细胞中获得的变化的“积分” 提供了一个新的研究方向来识别与21年龄和三体性生物学改变的年龄和三体性生物改变。细胞可以 通过微核（MN）形成和肉体外端粒电路（T-Circles）获取胞质DNA。一个 这种细胞质自动-DNA的子集由先天免疫监视途径认识到，这反过来 提高感应水平。我们假设三体第21三体增加了Mn水平和端粒损耗， 导致感应和甲基化改变的永久循环，频率积累/增加 随着年龄的增长。一种发现三体特异性变化的强大方法是评估生物学属性 在三体术21（MDS）的镶嵌患者的细胞中。一个人可以揭露并量化21诱导的三体性 通过在trisomic细胞中存在的等源性疾病细胞中观察到的“减去”值的变化（从而 消除由于总背景遗传构成以及环境影响而引起的混杂影响）。 为了确定三体性不平衡对胞质DNA途径的影响，我们将纵向比较 来自65例MDS 3个时间点的65人的等源性三体性细胞与疾病细胞的生物学测量， （包括基线数据，涵盖多达30年的随访）。为了检验我们的研究假设，我们将 量化：（1）通过MN分析的胞质自DNA； （2）亚电位/端粒变化或功能障碍； （3） 感应模式和细胞因子水平； （4）DNA甲基化模式。这些生物学因素中的每一个都将 使用我们开发/优化的“最先进”工具分析，其中包括：特定于染色体的测定法 Mn [天空/鱼类MN分析]）;新型的端粒/亚电位长度测定[Q-Fish＆Nanomapping]；端粒 功能障碍测定；感应，转录组和细胞因子标记物测定；全基因组研究DNA 甲基化；和生物信息学建模。我们还将收集/评估深度表型数据。通过审问 生物学措施与表型特征之间的关系，我们将发现它们在 调解健康结果。总而言之，这项对等源性三体/疾病细胞的纵向研究将使我们 “揭露”生物级联反应的21相关变化，并将提供首次评估 胞质DNA在与DS/MD相关的健康状况中的作用。通过识别驾驶员/调解员关系 在生物标志物之间，我们将创建新的算法，以帮助医生认识到健康状况 DS/MD的人的年龄较早。重要的是，我们将确定可以改变我们的新的治疗靶标 开发治疗方法以减轻MDS/DS患者获得的健康状况症状的方法。