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 年龄是大多数慢性病的主要危险因素;然而， 风险在很大程度上是未知的。老年疾病的一个统一特征是， 疾病和癌症是造血干细胞中的体细胞突变的获得（经常 DNMT 3A、TET 2、JAK 2），称为不确定潜能的克隆性造血（CHIP）。我会 利用人类基因组学来识别CHIP获取、克隆扩增 和疾病为什么只有一些个体发展CHIP，为什么只有一些CHIP克隆扩展， 为什么只有少数CHIP携带者发病目前尚不清楚。我假设 生殖系遗传变异有助于CHIP获得、克隆扩增和疾病。我 建议（1）在现有基因组测序数据中识别CHIP并进行遗传关联 分析超过80万人的CHIP，并评估CHIP相关变异如何改变 体外随访实验中人造血干细胞功能。(2)定义 CHIP克隆扩张的决定因素及其与疾病的关系。(3)识别基因表达 导致克隆扩张和疾病的程序。成功实现这些目标， 强调预防CHIP、克隆扩增和疾病的治疗靶点， 目前还没有治疗方法。这种CHIP治疗可能是一种干预， 多种衰老疾病为了实现这些目标，我将获得重要的机构支持， 从MGH包括资金，空间，保护时间和导师建立我的研究 组布罗德研究所将提供获得前沿基因组资源的机会。我会利用 我在这两个科学界的界面上的独特地位， 研究项目集中在CHIP。在完成了严格的基因组学培训后， 心血管生物学和临床医学，我现在准备利用这些技能，资源 和导师，毫不拖延地开始我自己的独立研究生涯。