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。

基本信息

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
项目类别：
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

项目摘要

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.

项目概要该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、骨髓血液疾病的危险因素恶性肿瘤和全因死亡率。 CHIP 被认为源自突变造血干细胞 (HSC) 携带致癌突变，赋予细胞更高的适应性，导致突变体的扩增克隆。携带 CHIP 相关突变的罕见造血克隆在健康人群中几乎无处不在个人。然而，CHIP 主要局限于老年人或有吸烟、化疗史的患者。或放射治疗暴露。这表明衰老和基因毒素所特有的生理扰动暴露，例如慢性炎症，是驱动 CHIP 所必需的。为了更好地了解 CHIP 的潜在机制，我们进行了小鼠研究，结果表明慢性 BM 中 IL-1 的产生是衰老和暴露于放射或化疗的常见结果。我们的初步数据表明，慢性 IL-1 会激活与 PU.1 诱导相关的细胞生长停滞程序长期 HSC (HSCLT)。引人注目的是，Tet2 缺陷的 HSCLT 未能在 IL-1 暴露。沿着这些思路，我们的数据表明，增加 Tet2 缺陷的克隆扩展需要慢性IL-1。这些初步数据表明突变型 HSC 的克隆扩增是一个新兴特征依赖于慢性炎症。这里提出的研究将识别和表征分子和细胞机制以 Tet2 缺陷为模型，慢性 IL-1 促进突变型 HSC 克隆扩增。调查路线将包括对暴露于 IL-1 的正常和 Tet2 缺陷型 HSC 进行分子和细胞分析，以及竞争性分析移植检测评估慢性 IL-1 对正常和 Tet2 缺陷 HSC 适应性的功能影响并排。最后，实验将评估 IL-1 阻断是否可以恢复正常的 HSC 健康状况以及逆转或限制克隆扩增。总而言之，我们的调查可以为重新定义 CHIP 提供基础：体细胞进化的潜在可逆过程，其中炎症性骨髓环境选择突变体 HSC 克隆。