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.

项目摘要 造血被认为是严格层次结构的血细胞形成的有序过程。 但是，现在很明显，内在和外在的细胞力影响一个复杂的细胞生态系统 分化。而复发突变会导致细胞自主性破坏在诸如克隆之类的美食性环境中 不确定电势（CHIP）和骨髓增生综合征（MDS）的造血症，克隆选择也是 取决于微环境中的外在力，例如炎症。在这种情况下，了解如何 恶性克隆的扰动对促炎性因素的反应在治疗中变得至关重要 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性造血。我们发现成熟先天的改变 免疫细胞有助于炎症环境，更具体地说是促进的因素 通过细胞内签名的差异激活，芯片突变克隆的克隆膨胀。基于我们 初步数据，我们提出，这种独特的细胞因子信号网络介导细胞功能，更多地介导 细胞代谢专门在突变干细胞中。野生型干细胞中相同的激活促进 分化和增殖，流量丧失。我们的研究确定了信号传感器和激活因子 转录3（STAT3）是介导芯片克隆功能的主要细胞内信号之一。正在进行 研究，我们将定义STAT3克隆细胞维持的特定机制。我们建议定义如何 细胞因子信号通路介导克隆膨胀（AIM 1）。我们将表征功能， 使用CHIP突变体前临床模型的造血干和祖细胞的转录特征 诱导和扰动以定义分子驱动因素以维持转化 炎症期间造血干细胞（AIM 2）。这些实验将定义新的监管网络 通过建立并将细胞因子与活动信号传导和细胞代谢联系起来。这些结果将提供 研究基础，了解克隆造血期间的炎症如何调节线粒体 具有选择性优势的代谢。这些发现将使我们能够利用这些相互作用来阻碍 通过改变骨髓微环境和靶向信号轴和细胞代谢来改变恶性克隆 （目标3）。向前迈进，这些发现可能导致治疗性干预措施，以改善细胞反应 减轻血液疾病中的碎屑和变化的结果。