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

项目概要/摘要 不确定潜能的克隆性造血（CHIP）是一种衰老相关的疾病， 进展为血液系统疾病的风险和总生存率降低。CHIP的发病率 随着年龄的增长而大幅增加，在70岁或以上的个体中存在10-15%。芯片是一 重大健康问题，因为预计美国≥ 65岁的个体比例 从2014年的15%增加到2060年的24%。CHIP是由体细胞突变引起的 这赋予造血干细胞（HSC）及其后代选择性优势， 用下一代测序技术检测出来然而，目前还没有方法来识别个人， 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 这项研究的目的是开发新的策略，以延长健康的造血功能在衰老过程中， 预防衰老相关的血液病。本提案的总体目标是确定 衰老相关的细胞和分子改变，促进CHIP突变克隆的扩增， 发展成血液系统紊乱基本原理是，基本机制将是主要的， 检测和缓解高风险CHIP的可修改目标。初步数据描述了技术上 创新的小鼠模型，其中CHIP发展和进展的时间可以严格控制。 这是迄今为止唯一一个能够重现体内CHIP进展的模型，因为它发生在人体中。使用此 模型中，老年骨髓（BM）微环境显示加速CHIP扩增， 进展，并与年龄相关的促炎细胞因子浓度的增加相关， BM微环境这些数据支持了中心假设，即老年BM的改变 微环境增加CHIP突变HSC及其后代引起CHIP的选择优势 扩展和进步。该项目将在老年小鼠中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扩展和进展期间的BM微环境; AIM 2。描述了各种机制， 老化BM微环境加速CHIP扩展和进展;和AIM 3.确定在何种程度 慢性炎症导致CHIP扩张和进展。该研究从概念上 创新，因为它是第一个定义老化BM微环境在引起CHIP中的重要作用的方法。 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进展为血液学疾病的基础机制，并为CHIP的治疗提供了基础。 开发预测高危CHIP的生物标志物和缓解CHIP的新型预防性治疗 进展

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.