Functional consequences of stem and progenitor cell heterogeneity

干细胞和祖细胞异质性的功能后果

• 批准号: 10188996
• 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
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-15 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10188996
• 关键词: Address; Aging; Alleles; Automobile Driving; Behavior; Blood; Blood Cells; CRISPR/Cas technology; Cells; Chromatin; Clone Cells; Clustered Regularly Interspaced Short Palindromic Repeats; Coupled; Data; Data Set; Databases; Development; Disease; Emerging Technologies; Epigenetic Process; Fishes; Foundations; Gene Expression; Genes; Genetic; Genetic Transcription; Genotoxic Stress; Goals; Health; Hematological Disease; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Heterogeneity; Human; Individual; Inflammatory; Intervention; Laboratories; Messenger RNA; Methods; Modeling; Molecular; Natural regeneration; Outcome; Output; Patients; Pharmacology; Physiological; Population Heterogeneity; Positioning Attribute; Process; Production; Recording of previous events; Regulator Genes; Research; Research Personnel; Resolution; Resource Sharing; Shapes; Stress; Techniques; Technology; Testing; Time; Transplantation; analytical tool; base; cell behavior; conflict resolution; data sharing; design; improved; in vivo; innovation; insight; mouse model; novel strategies; offspring; primitive cell; progenitor; programs; screening; small hairpin RNA; small molecule; stem; stem cells; therapy outcome; tool; transcriptome

OVERALL PROJECT SUMMARY This program brings together five hematopoiesis investigators who have been working collaboratively to address the fundamental question of how individual hematopoietic stem and progenitor cells (HSPC) are regulated to contribute to the production of blood under homeostatic and stress conditions. It creates a collective of complementary technologies developed in the investigator's laboratories to track individual clones in vivo and thereby to model how distinct clonal behaviors contribute to hematopoietic output under varying conditions. Furthermore, it employs innovative tools for manipulating specific molecular regulators of gene expression to test which molecules drive specific HSPC behaviors. These are tested in the context of inflammatory and genotoxic stress and are evaluated for their ability to alter the competitive relationship of normal HSPC with clones bearing blood disease associated alleles known to accumulate in the aging human. The cross comparison of models, species, time in development and molecular parameters (mRNA, meDNA, ncRNA, chromatin state) shared through an established common database and analytic tools provide a uniquely powerful means of defining with high resolution the process of hematopoiesis. By providing a mechanism to sustain interaction, share data and techniques and create a forum for resolution of conflicting data, this PO1 will facilitate the creation of a hematopoiesis `roadmap' whereby interventions at specific molecular waypoints can modulate blood cell production to enhance hematopoietic regeneration and limit aberrant clonal outgrowth in settings of disease.

项目总体概要 该计划汇集了五位造血研究人员，他们一直在合作研究 解决个体造血干细胞和祖细胞 (HSPC) 的基本问题 调节以有助于在稳态和应激条件下产生血液。它创建了一个 研究人员实验室开发的用于追踪个体克隆的补充技术的集合 体内，从而模拟不同的克隆行为如何在不同的条件下促进造血输出 状况。此外，它采用创新工具来操纵基因的特定分子调节剂 表达来测试哪些分子驱动特定的 HSPC 行为。这些是在以下背景下进行测试的 炎症和基因毒性应激，并评估它们改变竞争关系的能力 正常 HSPC 的克隆带有已知在老年人体内积累的血液疾病相关等位基因。 模型、物种、发育时间和分子参数（mRNA、meDNA、 ncRNA（染色质状态）通过已建立的通用数据库和分析工具共享，提供了 以高分辨率定义造血过程的独特强大手段。通过提供 维持互动、共享数据和技术并创建解决冲突论坛的机制 数据显示，该 PO1 将有助于创建造血“路线图”，从而在特定情况下进行干预 分子路径点可以调节血细胞的产生，以增强造血再生并限制 疾病环境下的异常克隆生长。