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，分裂细胞会获得DNA突变。这些躯体突变中的少数会议会议选择性 优势导致携带体突变的细胞的克隆增殖。在血液中，这个过程是 称为“克隆造血”。这些突变包括癌症驱动基因的两个点突变（例如克隆 不确定潜在的“芯片”的造血）和巨型尺度的删除，重复和复制中性 杂合性丧失（例如，镶嵌染色体改变，“ MCAS”）。芯片和MCA都已经 在60岁以上的5％的个人中检测到。尽管两者都可以预测寿命较短，但芯片会导致髓样偏置 干细胞分化，而MCA会导致淋巴样干细胞分化。结果，芯片和 MCA与感染，心血管疾病，癌症和其他疾病有不同的疾病关联 衰老。尽管芯片一直是重要的研究活动的领域，但我们所知的多个差距仍然存在 MCA及其对衰老和人口健康的影响。 MCA克隆扩展以组成更大的克隆 血液的比例预示着更严重的健康后果。但是，我们不知道为什么有些MCA克隆 但是其他人并没有扩展，哪些因素可以预测克隆扩张的速度以及膨胀率如何 与疾病结局。总体而言，我们假设MCA具有更高的克隆扩张率会议a 对健康的影响更大，并且扩大的承诺具有遗传和环境的基础 通过基因表达介导。解决这一差距的障碍是很少宣布的 纵向采样的血液集合。幸运的是，我们的团队有两个最近的成就使 美国解决这一差距：1）对67,000个全基因组中的MCAS调查，2） 计算方法来估算单个时间点的MCA扩展速率。在AIM 1中，我们将 通过利用独特的系列血样（相距19年）来衡量MCA扩展的速率 来自来自三个深层表型队列的729名患有MCA的人。在AIM 2中，我们将完善我们的方法 克隆扩张率估计并在人群规模上应用此方法来估计MCA克隆扩张 来自几个潜水员队列的130万个人的比率。我们将确定遗传和环境因素 易于克隆扩张并建立MCA克隆扩张与疾病之间的关系。在 AIM 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 MCAS并确定导致克隆扩张的途径。我们具有深厚专业知识的多学科团队 计算基因组学，统计，血液学和人类流行病学在这方面成功中毒了 努力。成功执行我们的目标将告知风险模型，以将MCA的个人分类为 个性化的预防，例如干预措施或增强筛查，并确定新的生物学途径 治疗发展的靶标。最后，我们的研究是对体细节镶嵌的见解的模型 血液以外的其他组织和疾病部位支持健康的衰老并改善人口健康。