Establishing the dynamics of lymphoid clonal hematopoiesis and its aging-related disease consequences

建立淋巴克隆造血的动态及其与衰老相关的疾病后果

• 批准号: 10713682
• 负责人: Paul L. Auer
• 金额: $ 77.94万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10713682
• 关键词: Address; Affect; Age; Aging; Area; Biological; Blood; Blood Cells; Blood specimen; Cardiovascular Diseases; Cell Lineage; Cell Proliferation; Cells; Chromosome abnormality; Chromosomes; Chronic Disease; Chronic Lymphocytic Leukemia; Clonal Expansion; Clonal Hematopoietic Stem Cell; Collection; Computing Methodologies; DNA; DNA Sequence Alteration; Data; Development; Disease; Disease Outcome; Environmental Risk Factor; Epidemiology; Gene Expression; Gene Expression Profile; Genes; Genetic; Genome; Genomic approach; Genomics; Health; Hematology; Hematopoiesis; Hematopoietic stem cells; Human; Immune; Individual; Infection; Inflammation; Inflammatory; Integration Host Factors; Intervention; Kidney Diseases; Knowledge; Lead; Learning; Longevity; Loss of Heterozygosity; Lung diseases; Lymphoid; Malignant Neoplasms; Maps; Measures; Mediating; Methods; Modeling; Molecular; Mosaicism; Multi-Ethnic Study of Atherosclerosis; Mutate; Mutation; Myelogenous; National Heart, Lung, and Blood Institute; Organism; Pathway interactions; Pattern; Phenotype; Pneumonia; Point Mutation; Population; Predictive Factor; Predisposing Factor; Process; Research Activity; Risk; Risk Factors; Sampling; Site; Somatic Mutation; Surveys; Time; Tissues; Trans-Omics for Precision Medicine; United States National Institutes of Health; Women' s Health; Work; biobank; blood fractionation; cardiovascular disorder risk; cardiovascular health; cell type; clinical phenotype; cohort; differential expression; disorder risk; genomic data; healthy aging; high risk; improved; individualized prevention; insight; molecular modeling; mortality; mosaic; multidisciplinary; novel; phenome; population health; programs; prospective; screening; single-cell RNA sequencing; statistics; stem cell differentiation; success; targeted treatment; therapeutic development; transcriptome sequencing; whole genome

Project Summary With age, dividing cells acquire DNA mutations. A small number of these somatic mutations confer a selective advantage leading to a clonal proliferation of cells harboring the somatic mutation. In blood, this process is termed ‘clonal hematopoiesis’. These mutations include both point mutations in cancer driver genes (eg. clonal hematopoiesis of indeterminate potential ‘CHIP’) and megabase-scale deletions, duplications and copy-neutral loss-of-heterozygosity (eg, mosaic chromosomal alterations, ‘mCAs’). CHIP and mCAs have each been detected in ~5% of individuals over 60. While both predict shorter lifespans, CHIP leads to a myeloid biased stem cell differentiation while mCAs lead to a lymphoid biased stem cell differentiation. As a result, CHIP and mCAs have distinct disease associations with infection, cardiovascular disease, cancer and other diseases of aging. Although CHIP has been an area of significant research activity, multiple gaps persist in our knowledge of mCAs and their impacts on aging and population health. mCA clones that expand to make up a larger proportion of the blood predict worse health consequences. However, we do not know why some mCA clones but not others expand, what factors predict the rate of clonal expansion and how rate of expansion associates with disease outcomes. Overall, we hypothesize that mCAs with higher rates of clonal expansion confer a greater impact on health and that the propensity to expand has genetic and environmental underpinnings that are mediated through gene expression. A barrier to addressing this gap is a paucity of large well-annotated collections of longitudinally-sampled blood. Fortuitously, our team has two recent accomplishments that enable us to address this gap: 1) a survey of mCAs in 67,000 whole genomes and 2) development of a novel computational method to estimate the rate of mCA expansion from single timepoints. In Aim 1, we will measure the rate of mCA expansion by leveraging unique serial blood samples (collected up to 19 years apart) from 729 individuals with mCAs from three deeply phenotyped cohorts. In Aim 2, we will refine our method for clonal expansion rate estimation and apply this method at population scale to estimate mCA clonal expansion rates in 1.3 million individuals from several diverse cohorts. We will identify genetic and environmental factors predisposing to clonal expansion and establish the relationship between mCA clonal expansion and disease. In Aim 3, we will analyze bulk and single-cell RNA-sequencing to ascertain the cell type specific biological impact of mCAs and identify pathways leading to clonal expansion. Our multidisciplinary team with deep expertise in computational genomics, statistics, hematology and human epidemiology is uniquely poised for success in this effort. Successful execution of our aims will inform risk models to stratify individuals with mCAs for personalized prevention, such as interventions or enhanced screening, and identify new biological pathways to target for therapeutic development. Finally, our study serves as a model for insights on somatic mosaicism in other tissues and disease sites beyond the blood to support healthy aging and improve population health.

项目摘要 随着年龄的增长，分裂的细胞会获得DNA突变。这些体细胞突变中的一小部分赋予了选择性 有利于携带体细胞突变的细胞的克隆性增殖。在血液中，这个过程是 被称为“克隆造血”。这些突变包括癌症驱动基因的点突变(例如。克隆性 不确定的潜在‘芯片’的造血作用)和百万碱基规模的缺失、复制和复制中性 杂合性缺失(例如，马赛克染色体改变，‘MCAS’)。CHIP和MCAS各自都被 在60岁以上的人中检出了~5%的人。虽然两者都预测寿命较短，但芯片会导致髓系偏向 干细胞分化，而MCAS导致偏向淋巴的干细胞分化。因此，芯片和 MCAS与感染、心血管疾病、癌症和其他疾病有明显的联系 衰老。尽管芯片一直是一个重要的研究活动领域，但我们的知识中仍然存在着多个缺口 MCAS及其对老龄化和人口健康的影响。MCA克隆可扩展以组成更大的 血液的比例预示着更糟糕的健康后果。然而，我们不知道为什么一些MCA克隆 但不是其他的扩张，什么因素预测克隆扩张的速度，以及扩张速度如何关联 与疾病结果有关。总体而言，我们假设克隆扩张率较高的MCAS赋予 对健康有更大的影响，而且这种扩大的倾向有遗传和环境的基础， 都是通过基因表达来调节的。弥补这一差距的一个障碍是缺乏大量有良好注释的 收集纵向采样的血液。幸运的是，我们的团队最近取得了两项成就，使 美国将解决这一差距：1)对67,000个全基因组进行MCAS调查；2)开发一种新的 从单个时间点估计MCA扩展速率的计算方法。在目标1中，我们将 利用独特的系列血液样本(相隔长达19年)测量大脑中动脉扩张的速度 来自三个表型较深的队列的729名MCAS患者。在目标2中，我们将改进我们的方法 克隆扩张率估计及其在种群规模估计MCA克隆扩展中的应用 来自几个不同队列的130万人的比率。我们将确定遗传和环境因素 易发生克隆性扩增，建立MCA克隆性扩增与疾病的关系。在……里面 目的3，我们将分析批量和单细胞rna测序，以确定细胞类型的特定生物学影响。 并确定导致克隆扩增的途径。我们的多学科团队在以下领域拥有深厚的专业知识 计算基因组学、统计学、血液学和人类流行病学在这方面独树一帜 努力。成功执行我们的目标将为风险模型提供信息，以便对患有MCAS的个人进行分层 个性化预防，如干预或加强筛查，并确定新的生物途径 治疗发展的目标。最后，我们的研究为深入了解体细胞嵌合体提供了一个模型。 血液以外的其他组织和疾病部位，以支持健康老龄化和改善人口健康。