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: 10645132
• 负责人: Jennifer Jean Trowbridge
• 金额: $ 47.28万
• 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/10645132
• 关键词: Acceleration; Age; Aging; Apoptosis; Automobile Driving; Biological; 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; Methods; Modeling; Molecular; Mus; Mutation; Myeloproliferative disease; Outcome; Pathogenicity; Patients; Population; Process; Proliferating; 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; biomarker identification; bone aging; cell type; cytokine; disorder risk; efficacy evaluation; hematopoietic stem cell expansion; high risk; human old age (65+); in vivo; innovation; mouse model; mutant; next generation sequencing; novel; novel strategies; nucleophosmin; prevent; progression risk; prophylactic; risk mitigation; 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.

项目摘要/摘要 不确定电势（CHIP）的克隆造血是一种与老化相关的疾病，供认增加了 进展为血液学障碍的风险和总体存活率降低。芯片事件 随着年龄的增长，有10-15％的70岁或以上的个人大大增加。芯片是一个 严重的健康问题，因为预计在美国的个人比例≥65岁 从2014年的15％增加到2060年的24％。芯片是由躯体突变引起的 该会议对造血干细胞（HSC）及其后代有选择性的优势，很容易 使用下一代测序检测。但是，目前尚无识别个人的方法 哪种芯片将发展为血液学障碍，并且没有疗法来防止这种进展。长期 这项研究的目标是制定新的策略，以扩展衰老期间健康的造血功能 预防衰老相关的血液学疾病。该提议的总体目的是确定 与衰老相关的细胞和分子改变，促进芯片突变克隆的扩展和 它们发展为血液学障碍。理由是，基本机制将是主要的， 可修改的目标，用于检测和缓解高风险芯片。初步数据在技术上描述了 可以严格控制芯片开发和进展时间的创新小鼠模型。 这是迄今为止唯一概括体内芯片进展的模型。使用此 模型，老化的骨髓（BM）微环境已显示可加速芯片膨胀和 进展，与年龄相关的促炎细胞因子浓度的升高相关 BM微环境。这些数据支持以下核心假设，即老年BM的改变 微环境增加了芯片突变的HSC的选择性优势及其进度引起的芯片 扩展和进展。该项目将在老年小鼠中使用细胞和分子生物学方法 达到以下特定目的：目标1。发现老年人选择的致病体细胞突变 芯片扩张和进展过程中的BM微环境；目标2。描述 老化的BM微环境会加速芯片的扩展和进展；和目标3。确定范围 慢性炎症会导致芯片扩张和进展。拟议的研究在概念上是 创新性是因为它是第一个定义老年BM微环境在引起芯片中的重要作用的重要作用 扩展和进展。这项研究很重要，因为它将定义细胞和分子 芯片发展为血液学障碍的机制，并为 生物标志物的开发以预测高风险芯片和新型预防疗法以减轻芯片 进展。

项目成果

New insight into the causes, consequences, and correction of hematopoietic stem cell aging.

对造血干细胞衰老的原因、后果和纠正的新见解。

• DOI: 10.1016/j.exphem.2023.07.002
• 发表时间: 2023
• 期刊: Experimental hematology
• 影响因子: 2.6
• 作者: Mansell,Els;Lin,DawnS;Loughran,StephenJ;Milsom,MichaelD;Trowbridge,JenniferJ
• 通讯作者: Trowbridge,JenniferJ

Hematopoietic stem cell aging and leukemia transformation.

• DOI: 10.1182/blood.2022017933
• 发表时间: 2023-08-10
• 期刊: BLOOD
• 影响因子: 20.3
• 作者: Diaz, Patricia A. Colom;Mistry, Jayna J.;Trowbridge, Jennifer J.
• 通讯作者: Trowbridge, Jennifer J.

Actinomycin D Targets NPM1c-Primed Mitochondria to Restore PML-Driven Senescence in AML Therapy.

• DOI: 10.1158/2159-8290.cd-21-0177
• 发表时间: 2021-12-01
• 期刊: Cancer discovery
• 影响因子: 28.2
• 作者: Wu HC;Rérolle D;Berthier C;Hleihel R;Sakamoto T;Quentin S;Benhenda S;Morganti C;Wu C;Conte L;Rimsky S;Sebert M;Clappier E;Souquere S;Gachet S;Soulier J;Durand S;Trowbridge JJ;Bénit P;Rustin P;El Hajj H;Raffoux E;Ades L;Itzykson R;Dombret H;Fenaux P;Espeli O;Kroemer G;Brunetti L;Mak TW;Lallemand-Breitenbach V;Bazarbachi A;Falini B;Ito K;Martelli MP;de Thé H
• 通讯作者: de Thé H

Hand in hand: intrinsic and extrinsic drivers of aging and clonal hematopoiesis.

• DOI: 10.1016/j.exphem.2020.09.197
• 发表时间: 2020-11
• 期刊: Experimental hematology
• 影响因子: 2.6
• 作者: SanMiguel JM;Young K;Trowbridge JJ
• 通讯作者: Trowbridge JJ