Project 3 - Transcriptional and epigenetic heterogeneity of stem/progenitor cells

项目 3 - 干/祖细胞的转录和表观遗传异质性

• 批准号: 10641542
• 负责人: DANIEL G TENEN
• 金额: $ 51.63万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-07 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10641542
• 关键词: Address; Affect; Assessment tool; Behavior; Biological Markers; Cell Line; Cell Maintenance; Cell Survival; Cell physiology; Cells; Characteristics; Chromatin; Clonal Expansion; Clonal Hematopoietic Stem Cell; Complex; Cytokine Signaling; DNA Methylation; DNMT3a mutation; Data; Data Analyses; Data Set; Diagnosis; Dysmyelopoietic Syndromes; Ecosystem; Environment; Epigenetic Process; Functional disorder; Gene Expression; Genetic Transcription; Glycolysis; Hematological Disease; Hematopoiesis; Hematopoietic stem cells; Heterogeneity; IL6 gene; Immune; Inflammation; Inflammatory; Kinetics; Lead; Link; MAP Kinase Gene; Maintenance; Malignant - descriptor; Maps; Marrow; Mediating; Metabolic; Metabolic Pathway; Metabolism; Methods; Mitochondria; Molecular; Mutation; Myelogenous; NF-kappa B; Outcome; Pattern; Population; Population Dynamics; Pre-Clinical Model; Preleukemia; Process; Proliferating; Proteomics; Publications; Recurrence; Research; Resolution; Risk; Role; Signal Pathway; Signal Transduction; Stat3 protein; Stimulus; Testing; Therapeutic; Therapeutic Intervention; Work; cancer cell; cell behavior; cell growth regulation; cytokine; data integration; data sharing networks; experimental study; extracellular; hematopoietic differentiation; hematopoietic stem cell expansion; improved; in vivo; inflammatory milieu; leukemic transformation; loss of function; metabolomics; mitochondrial metabolism; mouse model; mutant; p38 Mitogen Activated Protein Kinase; pre-clinical; premalignant; programs; response; stem; stem cells; stemness; transcription factor; transcriptomics

PROJECT SUMMARY Hematopoiesis has been considered an ordered process of blood cell formation from a strict hierarchy; however, it is now clear that intrinsic and extrinsic cellular forces influence a complex cellular ecosystem of differentiation. While recurrent mutations cause cell autonomous disruptions in pre-leukemic settings like clonal hematopoiesis of indeterminate potential (CHIP) and myelodysplastic syndrome (MDS), clonal selection is also dependent on extrinsic forces in the microenvironment like inflammation. In this context, understanding how perturbations in pre-malignant clones respond to pro-inflammatory factors becomes fundamental in therapeutic advancement. Our project seeks to establish a molecular and cellular framework for characterization of clonal and inflammatory hematopoiesis at single-cell resolution. We have found that alterations in mature innate immune cells contribute to a perturbed inflammatory environment, and more specifically factors that promote clonal expansion of CHIP mutant clones through differential activation of intracellular signlaing. Based on our preliminary data, we propose that this unique cytokine signaling network mediates cellular function and more so cellular metabolism specifically in mutant stem cells. The same activation in wild-type stem cells promotes differentiation and proliferation, with loss of stemness. Our research identified Signal Transducer And Activator Of Transcription 3 (STAT3) as one of the major intracellular signals mediating CHIP clonal function. In ongoing studies, we will to define STAT3 specific mechanisms of clonal cell maintenance. We propose to define how cytokine signaling pathways mediate clonal expansion (Aim 1). We will characterize the function and transcriptional characteristics of hematopoietic stem and progenitor cells using CHIP mutant pre-clinical models following induction and perturbation to define the molecular drivers for maintenance of transformed hematopoietic stem cells during inflammation (Aim 2). These experiments will define new regulatory networks by establishing and linking cytokine to active signaling and cellular metabolism. These results will provide the basis for studies to understand how inflammation during clonal hematopoiesis regulates mitochondrial metabolism for a selective advantage. These findings will allow us to exploit these interactions to impede pre- malignant clones by altering the marrow microenvironment and targeting signaling axis and cellular metabolism (Aim 3). Moving forward, these findings could lead to therapeutic interventions for improved cellular response mitigating CHIP and changing outcomes in hematological disease.

项目概要 造血被认为是按照严格的层次结构形成血细胞的有序过程。 然而，现在很清楚，内在和外在的细胞力影响复杂的细胞生态系统 差异化。虽然反复发生的突变会导致白血病前环境中的细胞自主破坏，例如克隆 不确定潜能造血（CHIP）和骨髓增生异常综合征（MDS），克隆选择也是如此 依赖于微环境中的外在力量，如炎症。在此背景下，了解如何 癌前克隆对促炎因子的干扰成为治疗的基础 进步。我们的项目旨在建立一个分子和细胞框架来表征克隆 和单细胞分辨率下的炎症造血作用。我们发现成熟先天的改变 免疫细胞会导致炎症环境受到干扰，更具体地说，是促进炎症的因素 通过细胞内信号传导的差异激活对 CHIP 突变体克隆进行克隆扩增。基于我们的 初步数据显示，我们认为这种独特的细胞因子信号网络介导细胞功能，更重要的是 细胞代谢，特别是在突变干细胞中。野生型干细胞中的相同激活促进 分化和增殖，同时失去干性。我们的研究确定了信号传感器和激活器 转录 3 (STAT3) 是介导 CHIP 克隆功能的主要细胞内信号之一。正在进行中 研究中，我们将定义STAT3克隆细胞维持的具体机制。我们建议定义如何 细胞因子信号通路介导克隆扩增（目标 1）。我们将描述该功能并 使用 CHIP 突变体临床前模型研究造血干细胞和祖细胞的转录特征 通过归纳和扰动来定义维持转化的分子驱动因素 炎症期间的造血干细胞（目标 2）。这些实验将定义新的监管网络 通过建立细胞因子并将其与活跃的信号传导和细胞代谢联系起来。这些结果将提供 了解克隆造血过程中炎症如何调节线粒体的研究基础 新陈代谢以获得选择性优势。这些发现将使我们能够利用这些相互作用来阻止预 通过改变骨髓微环境和靶向信号轴和细胞代谢来抑制恶性克隆 （目标 3）。展望未来，这些发现可能会导致改善细胞反应的治疗干预措施 减轻 CHIP 并改变血液疾病的结果。