Targeting Clonal Hematopoiesis of Indeterminate Potential using Human Genetics

利用人类遗传学靶向不确定潜力的克隆造血

• 批准号: 10685925
• 负责人: Alexander Bick
• 金额: $ 43.25万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10685925
• 关键词: Acceleration; Adult; Age; Aging; Biological; Biology; Cardiovascular Diseases; Cardiovascular system; Chronic Disease; Clinical Medicine; Clonal Expansion; Communities; Computing Methodologies; DNMT3a; Data; Development; Disease; Disease Outcome; Environmental Risk Factor; Funding; Gene Expression; Genes; Genetic Variation; Genome; Genomics; Germ-Line Mutation; Hematopoiesis; Hematopoietic Neoplasms; Hematopoietic stem cells; Human; Human Genetics; IL-6 inhibitor; IL6 gene; In Vitro; Individual; Institution; Interleukin-6; Internal Medicine; Intervention; JAK2 gene; Malignant Neoplasms; Mediating; Mentorship; Methods; Minority; Mutation; Myocardial Infarction; National Heart, Lung, and Blood Institute; Pathway interactions; Patients; Population; Positioning Attribute; Precision therapeutics; Prevention; Research; Residencies; Resources; Risk; Risk Factors; Sampling; Signal Transduction; Somatic Mutation; Testing; Therapeutic; Time; Training; Trans-Omics for Precision Medicine; Variant; Whole Blood; Work; cancer risk; career; cohort; disorder risk; experimental study; follow-up; genetic approach; genetic association; genome resource; genome sequencing; genome wide association study; human genomics; insight; mortality risk; mouse model; novel; prevent; programs; protective pathway; single-cell RNA sequencing; skills; stem cell function; therapeutic target; transcriptome sequencing

Project Summary Age is the dominant risk factor for most chronic diseases; yet mechanisms by which aging confers risk are largely unknown. One unifying feature of aging diseases as diverse as cardiovascular disease and cancer is the acquisition of somatic mutations in hematopoietic stem cells (frequently DNMT3A, TET2, JAK2), termed Clonal Hematopoiesis of Indeterminate Potential (CHIP). I will leverage human genomics to identify pathways underlying CHIP acquisition, clonal expansion and disease. Why only some individuals develop CHIP, why only some CHIP clones expand, and why only a minority of CHIP carriers develop disease is presently unknown. I hypothesize that germline genetic variation contributes to CHIP acquisition, clonal expansion and disease. I propose to (1) identify CHIP in existing genome sequencing data and perform genetic association analyses of CHIP in >800,000 individuals and evaluate how CHIP-associated variants alter human hematopoietic stem cell function in in-vitro follow-up experiments. (2) Define the determinants of CHIP clonal expansion and association with disease. (3) Identify gene expression programs that cause clonal expansion and disease. Successful execution of these aims will highlight therapeutic targets for the prevention of CHIP, clonal expansion and disease for which no therapies currently exist. Such a CHIP therapeutic would potentially be an intervention for multiple aging diseases. To succeed in these aims, I will receive significant institutional support from MGH including funding, space, protected time and mentorship to establish my research group. The Broad Institute will provide access to leading-edge genomic resources. I will leverage my unique position at the interface of these two scientific communities to establish a leading research program focused on CHIP. Having completed rigorous training in genomics, cardiovascular biology, and clinical medicine, I am now poised to leverage these skills, resources and mentorship to embark on my own independent research career without delay.

项目摘要 年龄是大多数慢性疾病的主要危险因素。然而，老化赋予的机制 风险在很大程度上未知。衰老疾病的一个统一特征，如心血管 疾病和癌症是造血干细胞中体细胞突变的获取（经常 DNMT3A，TET2，JAK2），称为不确定电势（CHIP）的克隆造血。我会 利用人类基因组学识别芯片获取的途径，克隆扩展 和疾病。为什么只有一些人会开发芯片，为什么只有一些芯片克隆扩展，而 为什么目前只有少数芯片携带者出现疾病。我假设这一点 种系遗传变异有助于获得芯片，克隆扩张和疾病。我 提议（1）识别现有基因组测序数据中的芯片并执行遗传关联 对> 800,000个个人中的芯片分析，并评估芯片相关的变体如何改变 人类造血干细胞在体外随访实验中的功能。 （2）定义 芯片克隆扩张和与疾病关联的决定因素。 （3）识别基因表达 导致克隆扩张和疾病的程序。这些目标的成功执行将 突出显示预防芯片，克隆扩张和疾病的治疗靶标 目前不存在治疗。这样的芯片治疗可能是干预 多种衰老疾病。为了取得成功，我将获得大量的机构支持 从MGH，包括资金，空间，受保护的时间和指导来建立我的研究 团体。广泛的研究所将提供获得领先基因组资源的访问。我会利用 我在这两个科学社区的界面上的独特地位，以建立领先 研究计划的重点是芯片。完成了严格的基因组学培训， 心血管生物学和临床医学，我现在准备好利用这些技能，资源 和指导能够毫不拖延地从事我自己的独立研究职业。