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: 10579836
• 负责人: Eric M Pietras
• 金额: $ 37.88万
• 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 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10579836
• 关键词: Address; Aging; Biological Assay; Bone Marrow; Cardiovascular Diseases; Cell Cycle; Cell Cycle Regulation; Cell Proliferation; Cells; Chemotherapy and/or radiation; Chimera organism; Chronic; Clonal Expansion; Clonal Hematopoietic Stem Cell; Coronary heart disease; Data; Down-Regulation; Endowment; 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; Proliferating; Protein Biosynthesis; Radiation therapy; Risk Factors; Role; Side; Signal Transduction; Smoking History; TAL1 gene; TP53 gene; Testing; Therapeutic; Tissues; Transplantation; Transplantation Conditioning; Up-Regulation; Work; cardiovascular risk factor; cell growth; cell growth regulation; 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 该提议的长期目标是确定促进克隆造血的机制 不确定电势（芯片）。芯片是心血管疾病，髓样血液学的危险因素 恶性和全因死亡率。芯片被认为是由突变造血干细胞（HSC）引起的 携带致癌突变，可赋予细胞的适应性增加，从而导致突变体的膨胀 克隆。在健康中，带有芯片相关突变的罕见造血克隆几乎是普遍的 个人。但是，CHIP在很大程度上限于年龄较大的人或有吸烟史的患者 或放疗暴露。这表明生理扰动是衰老和遗传毒素独有的 驱动芯片需要暴露（例如慢性炎症）。 为了更好地了解芯片的基础机制，我们进行了小鼠研究，表明了慢性 BM中的IL-1产生是衰老和暴露于放射或化学疗法的普遍结果。我们的 初步数据表明，慢性IL-1激活了与PU.1诱导有关的细胞生长停滞计划 长期HSC（HSCLT）。令人惊讶的是，TET2缺乏的HSCLT无法完全激活该增长逮捕计划 IL-1暴露。沿着这些线，我们的数据表明，增加TET2缺乏克隆的膨胀需要 慢性IL-1。这些初步数据表明，突变体HSC的克隆扩张是新兴的特征 取决于慢性炎症。 这里提出的研究将识别和表征分子和细胞机制 慢性IL-1使用TET2缺乏效率作为模型促进突变HSC克隆扩张。调查线 将包括暴露于IL-1的正常和TET2缺陷HSC的分子和细胞分析，并具有竞争力 移植测定以评估慢性IL-1对正常和TET2缺陷HSC Fitness的功能影响 并排。最后，实验将评估IL-1封锁是否可以恢复正常的HSC健身和 反向或限制克隆膨胀。总之，我们的调查可以为重新定义芯片作为一个基础 炎症性BM环境为突变体选择的躯体进化过程可能可逆的过程 HSC克隆。