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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：
10391755
负责人：
Eric M Pietras
金额：
$ 3.84万
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 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10391755
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/antagonist 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.

项目总结