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

项目摘要/摘要 克隆性造血不确定潜能(CHIP)是一种与衰老相关的疾病，可导致 有发展为血液系统疾病的风险，总体存活率下降。切屑的发生率 随着年龄的增长显著增加，在70岁或70岁以上的人中存在10%-15%。芯片是一种 严重的健康问题，因为美国65岁的个人≥比例预计将 从2014年的15%增加到2060年的24%。芯片是由体细胞突变引起的 这为造血干细胞(HSCs)及其后代提供了选择性优势，这很容易 使用下一代测序检测到。然而，目前还没有识别个人身份的方法 哪种芯片会发展成血液疾病，而且没有治疗方法可以阻止这种进展。长期的 这项研究的目标是开发新的策略，以延长健康的造血功能在衰老和 预防与衰老相关的血液疾病。这项提案的总体目标是确定 与衰老相关的细胞和分子改变，促进芯片突变克隆和 他们会发展成血液病。其基本原理是，潜在的机制将是主要的， 用于检测和缓解高危芯片的可修改目标。初步数据描述了技术上的 创新的鼠标模型，可以严格控制芯片开发和进度的时间。 这是迄今为止唯一一个可以概括人类体内芯片进展的模型。使用这个 模型显示，老化的骨髓微环境加速了芯片的扩张和 进展，并与年龄相关的促炎细胞因子浓度增加相关 BM的微环境。这些数据支持了一个中心假设，即老年BM的改变 微环境增加CHIP突变型HSCs及其后代对CHIP的选择优势 扩张和进步。该项目将在老年小鼠身上使用细胞和分子生物学方法来 实现以下具体目标：目的1.发现老年人选育的致病性体细胞突变(S 芯片扩展和进展过程中的BM微环境；目的2.描述BM的机制 老化的BM微环境加速芯片的扩展和进展；以及目标3.确定 慢性炎症会导致芯片扩张和进展。拟议的研究是概念性的 创新是因为它第一次定义了老化的BM微环境在导致芯片中的重要作用 扩张和进步。这项研究意义重大，因为它将定义细胞和分子 CHIP进展为血液系统疾病的基础机制，并为 预测高危CHIP的生物标志物和缓解CHIP的新型预防疗法的发展 进步。

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.