Discovery of Aging-Associated Mechanisms Causing Expansion and Progression of Clonal Hematopoiesis of Indeterminant Potential (CHIP)

发现导致不确定潜能克隆造血（CHIP）扩张和进展的衰老相关机制

• 批准号: 10425388
• 负责人: Jennifer Jean Trowbridge
• 金额: $ 47.07万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10425388
• 关键词: Age; Aging; Apoptosis; Automobile Driving; Biological; Biological Markers; Blood; Blood Cells; Bone Marrow; Cells; Chronic; Clinical; Clonal Expansion; Complex; DNA Damage; DNA Modification Methylases; DNMT3a; Data; Detection; Development; Elderly; Enzyme-Linked Immunosorbent Assay; Epigenetic Process; Flow Cytometry; Goals; Growth Factor; Health; Hematological Disease; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Human; Incidence; Individual; Inflammation; Inflammatory; MAP Kinase Gene; Macrophage Colony-Stimulating Factor; Methods; Modeling; Molecular; Mus; Mutation; Myeloproliferative disease; Outcome; Pathogenicity; Patients; Population; Process; Public Health; Publishing; Ras/Raf; Research; Risk; Role; Signal Transduction; Somatic Mutation; Survival Rate; System; TNF gene; Testing; Therapeutic; Time; Tissues; United States; Work; age related; aged; biomarker development; bone aging; cell type; cytokine; disorder risk; hematopoietic stem cell expansion; high risk; human old age (65+); in vivo; innovation; mouse model; mutant; next generation sequencing; novel; novel strategies; nucleophosmin; prevent; prophylactic; transcriptome sequencing

PROJECT SUMMARY/ABSTRACT Clonal hematopoiesis of indeterminant potential (CHIP) is an aging-associated condition that confers increased risk of progression to hematologic disorder and a decreased overall survival rate. The incidence of CHIP increases substantially with advancing age, present in 10-15% of individuals aged 70 years or older. CHIP is a significant health concern as the proportion of individuals ≥ 65 years old in the United States is expected to increase from 15% of the population in 2014 to 24% by the year 2060. CHIP is caused by somatic mutations that confer a selective advantage to hematopoietic stem cells (HSCs) and their progeny, which can be easily detected using next-generation sequencing. However, there are currently no methods to identify individuals in which CHIP will progress to hematologic disorder, and no therapies to prevent this progression. The long-term goal of this research is to develop novel strategies to extend healthy hematopoietic function during aging and prevent aging-associated hematologic disorders. The overall objective of this proposal is to determine the aging-associated cellular and molecular alterations that promote the expansion of CHIP-mutant clones and their progression to hematologic disorder. The rationale is that the underlying mechanisms will be prime, modifiable targets for detection and mitigation of high-risk CHIP. Preliminary data describe a technically innovative mouse model in which the timing of CHIP development and progression can be strictly controlled. This is the only model to date that recapitulates in vivo CHIP progression as it occurs in humans. Using this model, the aged bone marrow (BM) microenvironment was shown to accelerate CHIP expansion and progression, and correlated with an age-related increase in the concentration of pro-inflammatory cytokines in the BM microenvironment. These data support the central hypothesis that alterations in the aged BM microenvironment increase the selective advantage of CHIP-mutant HSCs and their progeny causing CHIP expansion and progression. This project will use cellular and molecular biological approaches in aged mice to achieve the following specific aims: AIM 1. Discover pathogenic somatic mutation(s) selected for by an aged BM microenvironment during CHIP expansion and progression; AIM 2. Delineate the mechanisms by which the aged BM microenvironment accelerates CHIP expansion and progression; and AIM 3. Determine the extent to which chronic inflammation causes CHIP expansion and progression. The proposed research is conceptually innovative because it is the first to define the important role of the aged BM microenvironment in causing CHIP expansion and progression. This study is significant because it will define the cellular and molecular mechanisms that underlie progression of CHIP to hematologic disorder and provide a fundamental basis for the development of biomarkers to predict high-risk CHIP and novel prophylactic therapies to mitigate CHIP progression.

项目概要/摘要 不确定潜能克隆造血 (CHIP) 是一种与衰老相关的疾病，可导致细胞因子增加 进展为血液疾病的风险和总体生存率降低。 CHIP 的发生率 随着年龄的增长而显着增加，70 岁或以上的人中有 10-15% 存在这种情况。芯片是一个 预计美国 65 岁以上人口的比例将成为重大健康问题 到 2060 年，这一比例将从 2014 年的 15% 增加到 24%。CHIP 是由体细胞突变引起的 赋予造血干细胞 (HSC) 及其后代选择性优势，可以很容易地 使用下一代测序检测。但目前还没有方法可以识别个体身份 CHIP 将进展为血液系统疾病，并且没有治疗方法可以阻止这种进展。长期来看 这项研究的目标是开发新的策略，以在衰老和衰老过程中延长健康的造血功能。 预防与衰老相关的血液系统疾病。该提案的总体目标是确定 与衰老相关的细胞和分子改变促进 CHIP 突变克隆的扩增 他们进展为血液系统疾病。理由是底层机制将是首要的， 用于检测和缓解高风险 CHIP 的可修改目标。初步数据描述了技术 创新的小鼠模型，可以严格控制 CHIP 发育和进展的时间。 这是迄今为止唯一能够重现人类体内 CHIP 进展的模型。使用这个 模型中，老化的骨髓 (BM) 微环境被证明可以加速 CHIP 扩展并 进展，并与年龄相关的促炎细胞因子浓度增加相关 BM 微环境。这些数据支持了中心假设，即老年 BM 的变化 微环境增加了 CHIP 突变型 HSC 及其后代的选择优势，导致 CHIP 扩展和进步。该项目将在老年小鼠身上使用细胞和分子生物学方法 实现以下具体目标： 目标 1. 发现老年人选择的致病性体细胞突变 CHIP 扩展和进展过程中的 BM 微环境；目标 2. 描述机制 老化的BM微环境加速CHIP扩展和进展；和目标 3. 确定程度 慢性炎症会导致 CHIP 扩张和进展。拟议的研究在概念上是 创新性在于它首次定义了老化的骨髓微环境在导致 CHIP 中的重要作用 扩展和进步。这项研究意义重大，因为它将定义细胞和分子 CHIP 进展为血液疾病的机制，并为 开发预测高风险 CHIP 的生物标志物和减轻 CHIP 的新型预防性疗法 进展。