Impact of IL-1 signaling on hematopoietic stem cell function and emergence of clonal hematopoiesis.

IL-1 信号传导对造血干细胞功能和克隆造血出现的影响。

• 批准号: 10507242
• 负责人: Eric M Pietras
• 金额: $ 5.12万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10507242
• 关键词: Address; Aging; Biological Assay; Bone Marrow; Cardiovascular Diseases; Cell Cycle; Cell Proliferation; Cells; Chimera organism; Chronic; Clonal Expansion; Clonal Hematopoietic Stem Cell; Coronary heart disease; Data; Down-Regulation; Environment; Evolution; Exposure to; Failure; Gene Expression Regulation; Genes; Goals; Growth; Hematologic Neoplasms; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Homeostasis; Individual; Inflammation; Inflammatory; Interleukin-1; Investigation; Modeling; Molecular; Molecular Analysis; Mus; Mutagens; Mutation; Myelogenous; Myeloid Leukemia; Myeloproliferative disease; Oncogenic; Patients; Physiological; Process; Production; Protein Biosynthesis; Radiation; Radiation therapy; Risk Factors; Role; Side; Signal Transduction; Smoking History; TAL1 gene; TP53 gene; Testing; Therapeutic; Tissues; Transplantation; Transplantation Conditioning; Up-Regulation; Work; base; cardiovascular risk factor; cell growth; chemotherapy; cytokine; experimental study; fitness; hematopoietic stem cell expansion; hematopoietic stem cell quiescence; high risk; in vivo; inhibitor; innovation; loss of function mutation; mortality; mutant; novel; prevent; programs; senescence; stem cell function; stem cell growth

PROJECT SUMMARY The long-term objective of this proposal is to identify mechanism(s) that promote clonal hematopoiesis of indeterminate potential (CHIP). CHIP is a risk factor for cardiovascular disease, myeloid hematological malignancy, and all-cause mortality. CHIP is thought to arise from mutant hematopoietic stem cells (HSC) carrying oncogenic mutations that endow the cells with increased fitness, leading to expansion of the mutant clone. Rare hematopoietic clones carrying CHIP-associated mutations are near-ubiquitous in healthy individuals. However, CHIP is largely confined in older individuals or patients with a history of smoking, chemo- or radiotherapy exposure. This suggests that physiological perturbation(s) unique to aging and genotoxin exposure, such as chronic inflammation, are required to drive CHIP. To better understand the mechanism underlying CHIP, we have conducted mouse studies that indicate chronic IL-1 production in the BM is a common consequence of aging and exposure to radiation or chemotherapy. Our preliminary data show that chronic IL-1 activates a cell growth arrest program associated with PU.1 induction in long-term HSC (HSCLT). Strikingly, Tet2-deficient HSCLT fail to fully activate this growth arrest program during IL-1 exposure. Along these lines, our data show that increased Tet2-deficient clonal expansion requires chronic IL-1. These preliminary data suggest that clonal expansion of mutant HSC is an emergent feature dependent on chronic inflammation. The studies proposed here will identify and characterize the molecular and cellular mechanisms by which chronic IL-1 promotes mutant HSC clonal expansion, using Tet2-deficiency as a model. Lines of investigation will include molecular and cellular analyses of normal and Tet2-deficient HSC exposed to IL-1, and competitive transplant assays to assess the functional impact of chronic IL-1 on normal and Tet2-deficient HSC fitness side-by-side. Lastly, experiments will assess whether IL-1 blockade can restore normal HSC fitness and reverse or limit clonal expansion. Altogether, our investigations could provide a basis for redefining CHIP as a potentially reversible process of somatic evolution in which an inflammatory BM environment selects for mutant HSC clones.

项目摘要 这项提案的长期目标是确定促进克隆造血的机制， 不确定电位（CHIP）。CHIP是心血管疾病、骨髓造血系统疾病、 恶性肿瘤和全因死亡率。CHIP被认为是由突变的造血干细胞（HSC）引起的。 携带致癌突变，赋予细胞增加的适应性，导致突变体的扩增 分身携带CHIP相关突变的罕见造血克隆在健康人中几乎无处不在。 个体然而，CHIP在很大程度上局限于老年人或有吸烟史、化疗史、 或放射治疗暴露。这表明衰老和遗传毒性所特有的生理扰动 暴露，如慢性炎症，需要驱动CHIP。 为了更好地理解CHIP的机制，我们进行了小鼠研究，表明慢性CHIP BM中的IL-1产生是衰老和暴露于辐射或化学疗法的常见结果。我们 初步数据显示，慢性IL-1激活与PU.1诱导相关的细胞生长停滞程序， 长期HSC（HSCLT）。令人惊讶的是，Tet 2缺陷HSCLT未能完全激活这一生长停滞程序， IL-1暴露。沿着这些线，我们的数据表明，增加Tet 2缺陷克隆扩增需要 慢性IL-1。这些初步数据表明，突变型HSC的克隆扩增是一个紧急的特点， 依赖于慢性炎症 这里提出的研究将确定和表征分子和细胞机制， 慢性IL-1促进突变型HSC克隆扩增，使用Tet 2缺陷作为模型。调查路线 将包括暴露于IL-1的正常和Tet 2缺陷HSC的分子和细胞分析，以及竞争性 评估慢性IL-1对正常和Tet 2缺陷型HSC适应性的功能影响的移植试验 肩并肩最后，实验将评估IL-1阻断是否可以恢复正常的HSC适应性， 逆转或限制克隆扩增。总之，我们的调查可以为重新定义CHIP作为一种 潜在可逆的体细胞进化过程，其中炎症BM环境选择突变体 HSC克隆。