Molecular regulation of native hematopoiesis

天然造血的分子调控

• 批准号: 10541825
• 负责人: Fernando Camargo
• 金额: $ 71.41万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-15 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10541825
• 关键词: Address; Affect; Age; Aging; Apical; Automobile Driving; Bar Codes; Behavior; Biological; Biological Assay; Biology; Blood; Bone Marrow Transplantation; Cell Lineage; Cells; Chromatin; Clonal Expansion; Coupled; Data; Disease; Dissection; Funding; Genetic; Genetic Transcription; Hematological Disease; Hematology; Hematopoiesis; Hematopoietic; Hematopoietic Stem Cell heterogeneity; Hematopoietic stem cells; Heterogeneity; Human; Impairment; In Situ; Individual; Interdisciplinary Study; Knowledge; Label; Lentivirus; Link; Maintenance; Marrow; Measurement; Modeling; Molecular; Mus; Natural regeneration; Organism; Outcome; Output; Physiological; Physiology; Population; Process; Property; Regulation; Research; Resolution; Source; System; Testing; Time; Transplantation; Work; aged; cell behavior; clinically relevant; epigenomics; functional outcomes; genetic approach; hematopoietic stem cell aging; insight; novel; premalignant; prevent; progenitor; single-cell RNA sequencing; stem; stem cell function; stem cells; tool; transcription factor; transcriptomics

SUMMARY Decades of work have established a paradigm for hematopoietic regeneration and maintenance based on the activity of multipotent hematopoietic stem cells (HSCs) at its apex. Our understanding of the fundamental properties of HSCs and progenitor populations has been historically based on notions derived from transplantation assays. Data over the last few years, however, have challenged the most fundamental aspects of models based on these studies, and have raised biological questions that are of direct clinical relevance in the hematology field. Additionally, it is now clear that intrinsic heterogeneity exists among seemingly pure populations of HSCs and downstream progenitors. How the functionally distinct behavior of these stem/progenitor cells is molecularly regulated and how individual clone size is controlled over time represent important biological questions relevant to our understanding of normal and diseased hematopoiesis. Over the past five years, my lab has developed novel single cell-based lineage tracing systems to study hematopoietic biology in the non-transplanted individual, which we refer to as native hematopoiesis. With these tools, we have shown that important biological differences exist between the source of hematopoietic cells and their outcomes when comparing transplantation versus native blood physiology. More recently, we have coupled lineage output readouts with molecular measurements at the single cell level, allowing us to identify transcriptional features of stem/progenitor cells that carry distinct functional outcomes. In this renewal application, we aim to utilize these high-resolution lineage-tracing tools to further characterize drivers of functional HSC heterogeneity and aging in native hematopoiesis. First, we will functionally and molecularly characterize a novel transcriptional regulator of the native HSC state, which we have identified using our singe cell screens. Second, we will utilize a combination of single cell lineage tracing, transcriptomics, and epigenomics to understand the molecular changes and clonal fluctuations that occur during the aging process in the mouse. Third, we will adapt our single cell molecular tracing strategies to characterize human hematopoiesis in a surrogate native state, and to identify potential novel regulators of human HSC behavior. Our comprehensive and interdisciplinary studies will shed led on the cellular and molecular mechanisms driving hematopoiesis in situ. Moreover, these studies will inform efforts to enhance hematopoietic regeneration and prevent pre-malignant clonal hematopoiesis.

总结 几十年的工作已经建立了一个基于造血干细胞的再生和维持的范例。 多能造血干细胞（HSC）在其顶端的活性。我们对基本的理解 HSC和祖细胞群体的特性在历史上一直基于来自以下的概念： 移植试验然而，过去几年的数据对最基本的方面提出了挑战。 基于这些研究的模型，并提出了与临床直接相关的生物学问题， 血液学领域此外，现在很清楚，内在的异质性存在于看似纯 HSC和下游祖细胞的群体。这些功能上不同的行为 干/祖细胞是分子调节的，个体克隆大小如何随时间控制代表了 重要的生物学问题有关我们的理解正常和患病的造血。来 在过去的五年里，我的实验室开发了新的基于单细胞的谱系追踪系统来研究造血 非移植个体的生物学，我们称之为天然造血。有了这些工具，我们 已经表明，重要的生物学差异存在于造血细胞的来源和它们的来源之间。 比较移植与自体血液生理学的结果。最近，我们将 谱系输出读数与单细胞水平的分子测量，使我们能够识别 干/祖细胞的转录特征携带不同的功能结果。在这次更新中， 应用程序，我们的目标是利用这些高分辨率的谱系追踪工具，以进一步表征驱动程序， 功能性HSC异质性和天然造血中的老化。首先，我们将在功能上和 分子特征的天然HSC状态，我们已经确定了一种新的转录调节因子 使用我们的单细胞屏幕。第二，我们将利用单细胞谱系追踪， 转录组学和表观基因组学，以了解发生的分子变化和克隆波动 在老鼠的衰老过程中。第三，我们将调整我们的单细胞分子追踪策略， 表征在替代天然状态下的人造血，并鉴定潜在的新的造血调节因子。 人类HSC行为我们的综合性和跨学科的研究将在细胞和 原位造血的分子机制此外，这些研究将为加强 造血再生和防止癌前克隆性造血。