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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结