Clonal tracking and molecular characterization of hematopoiesis under stress

应激条件下造血的克隆追踪和分子特征

基本信息

批准号：
10413504
负责人：
David T Scadden
金额：
$ 5.04万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-15 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10413504
关键词：
Address Age Animal Model Behavior Blood Cells Blood Flow Cytometry Bone Marrow CRISPR screen Cells Characteristics Clonal Expansion Clonal Hematopoietic Stem Cell Clone Cells Collection Data Development Disadvantaged Disease Dysmyelopoietic Syndromes Engineering Epigenetic Process Equilibrium Fluorescence Frequencies Gene Expression Gene Expression Profile Gene Expression Profiling Genetic Genotoxic Stress Goals Habits Hematological Disease Hematology Hematopoiesis Hematopoietic Hematopoietic stem cells Heterogeneity Human Individual Inflammatory Intervention Kinetics Label Laboratories Lesion Lymphoid Methods Molecular Molecular Analysis Molecular Profiling Mus Mutation Myelogenous Neoplasms Normal Cell Phenotype Population Production Radiation Regulator Genes Research Resolution Retrotransposon Risk Stimulus Stress System Techniques Testing Time Transplantation Zebrafish base collaborative approach comparative genotoxicity improved in vivo insight mortality mutant novel offspring premalignant primitive cell progenitor response small hairpin RNA stem cells

项目摘要

RESEARCH SUMMARY Hematopoiesis is now recognized as the integrated activity of multiple, largely progenitor clones with heterogeneous behavior. Clonal complexity is thought to diminish with age and human studies suggest that oligoclonal hematopoiesis with disease associated mutations is common. The presence of such clones incurs a substantial risk of hematologic neoplasia and all cause mortality. The overall goal of this proposal is to understand the molecular drivers of clonal behavior under stress conditions and to test whether modifying those drivers is capable of changing the relative competitive balance of normal and abnormal, risk bearing clones in animal models. We will use techniques of fluouresence clonal tracking in the mouse developed by us and compare these with retrotransposon clonal marking techniques in the mouse of Carmago and fluorescence clonal tracking techniques in the zebrafish developed by Zon. Further, we will characterize genetic characteristics of clones at single cell resolution using techniques of Tenen and define ncRNA candidate molecular drivers with Tenen. Finally, we will target epigenetic modifiers defined by Orkin, Tenen and Zon to test the impact on clonal competition between normal and mutant clones in vivo. Combined these complementary and collaborative approaches will point to methods for altering competitive relationships in hematopoiesis in favor of normal cells.

研究摘要现在，造血被认为是多个，主要祖细胞克隆的综合活性异质行为。克隆复杂性被认为随着年龄和人类研究而减少，表明与疾病相关突变的寡克隆造血症很常见。这种克隆的存在会产生血液学肿瘤的很大风险，所有人都会导致死亡率。该提议的总体目标是了解应力条件下克隆行为的分子驱动因素，并测试是否修改这些驱动程序能够改变正常和异常，风险轴承的相对竞争平衡动物模型中的克隆。我们将在我们开发的鼠标中使用氟克隆跟踪技术并将其与Carmago小鼠和 Zon开发的斑马鱼中的荧光克隆跟踪技术。此外，我们将描述使用Tenen的技术在单细胞分辨率下克隆的遗传特征并定义NCRNA 与Tenen的候选分子驱动器。最后，我们将瞄准由Orkin定义的Tenen定义的表观遗传修饰符和ZON，以测试体内正常克隆和突变克隆之间对克隆竞争的影响。将这些结合在一起互补和协作方法将指出改变竞争关系的方法造血支持正常细胞。