Molecular regulation of native hematopoiesis

天然造血的分子调控

• 批准号: 10157107
• 负责人: Fernando Camargo
• 金额: $ 72.75万
• 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/10157107
• 关键词: Address; Affect; Age; Aging; 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; Play; Population; Process; Property; Regulation; Research; Resolution; Role; Source; System; Testing; Time; Transplantation; Work; aged; base; 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.

概括 数十年的工作已经建立了基于造血再生和维持的范式 多能造血干细胞（HSC）在其顶点的活性。我们对基本的理解 HSC和祖先种群的特性一直是基于从 移植测定。但是，在过去几年中的数据挑战了最基本的方面 基于这些研究的模型，并提出了在 血液学领域。此外，现在很明显，在看似纯净的异质性 HSC和下游祖细胞的种群。这些功能上不同的行为 茎/祖细胞受到分子调节，并且随着时间的流逝如何控制单个克隆大小 与我们对正常和患病造血的理解有关的重要生物学问题。在 过去五年，我的实验室开发了新型的单细胞谱系追踪系统来研究造血 非移植个体的生物学，我们称为天然造血。使用这些工具，我们 已经表明，造血细胞的来源之间存在重要的生物学差异 比较移植与天然血液生理学时的结果。最近，我们耦合了 谱系输出读数在单细胞水平上具有分子测量，使我们能够识别 带有不同功能结果的茎/祖细胞的转录特征。在此续约中 应用程序，我们旨在利用这些高分辨率谱系追踪工具来进一步表征 本地造血的功能性HSC异质性和衰老。首先，我们将在功能上和 分子表征了天然HSC状态的新型转录调节剂，我们已经鉴定出来 使用我们的单细胞屏幕。其次，我们将利用单细胞谱系跟踪的组合， 转录组学和表观基因组学了解分子的变化和克隆波动 在老鼠的老化过程中。第三，我们将使我们的单细胞分子跟踪策略适应 特征在替代本地状态下人类造血症，并确定潜在的新型调节剂 人类HSC行为。我们的全面和跨学科研究将引起细胞和 分子机制原位驱动造血作用。此外，这些研究将为加强努力提供努力 造血再生并预防恶性前克隆造血。