Defining regulators of hematopoietic stem cell self-renewal and lineage potential

定义造血干细胞自我更新和谱系潜力的调节因子

基本信息

项目摘要

PROPOSAL SUMMARY The goal of my proposal is to understand the mechanisms regulating the self-renewal and lineage potential of hematopoietic stem cells (HSCs) and how HSC fate and function can be controlled by manipulation of epigenetic parameters. The context of my study is unique, because we have discovered a fetal, developmentally restricted HSC (drHSC) with unusual properties: the drHSCs are capable of long-term, multilineage reconstitution (LTMR) upon serial transplantation, but do not persist into adulthood during normal development. The ability of drHSCs to self-renew and persist is therefore induced upon transplantation. Further, while capable of generating all the “traditional” hematopoietic cell types investigated to date, the drHSCs are lymphoid biased and have superior B1a cell reconstitution capacity compared to the co-existing fetal liver (FL) HSCs. Amazingly, the lymphoid bias and B1a capacity are retained over many months in serial transplantation experiments. The two core properties that define functional HSCs – self-renewal and lineage potential – are therefore uniquely regulated in drHSCs. I will leverage these unique properties to understand the molecular and epigenetic mechanisms that govern HSC fate and function, and how these mechanisms are both stable (as in the case of drHSC lineage potential) and dynamic (as in the case of induced persistence). I will also take advantage of my ability to isolate three distinct populations of HSCs: the drHSCs, co-existing fetal HSCs (fHSCs), and adult HSCs (aHSCs). Together, this will enable me to ask fundamental questions in HSC biology from a unique perspective and with novel strategies: How is long-term persistence of drHSCs induced upon transplantation, whereas their lineage bias is retained? Is lineage potential exclusively a loss-of-function phenomenon or do adult HSCs have differentiation capabilities that fetal HSCs lack? If so, how are these gained? How can one HSC population be “reprogrammed” into another HSC subtype? I propose to pursue these questions by assessing epigenetic and transcriptome dynamics (Aim 1), and by functionally manipulating HSC potential using CRISPRi mouse models (Aim 2). Outcomes from this proposal will be provide fundamental proof-of-concept experiments for HSC manipulation with the long-term goal of applying these tools to increase the efficacy of stem cell transplant therapies.
提案摘要 我的建议的目标是了解调节自我更新和血统潜力的机制, 造血干细胞(HSC)以及HSC的命运和功能如何通过操纵造血干细胞来控制。 表观遗传参数我的研究背景是独一无二的,因为我们发现了一个胎儿, 具有不寻常特性的发育受限HSC(drHSC):drHSC能够长期, 多系重建(LTMR)在连续移植,但不持续到成年期正常 发展因此,在移植时诱导了drHSC自我更新和持续的能力。 此外,虽然能够产生迄今为止研究的所有“传统”造血细胞类型,但是, drHSC是淋巴偏向性的,并且与共存的造血干细胞相比具有上级B1 a细胞重建能力。 胎肝(FL)HSC。令人惊讶的是,淋巴偏向和B1 a能力连续数月保持不变。 移植实验定义功能性HSC的两个核心特性-自我更新和 因此,在drHSC中独特地调节。我将利用这些独特的属性, 了解控制HSC命运和功能的分子和表观遗传机制,以及这些机制如何影响HSC的功能。 这些机制是稳定的(如在drHSC谱系潜力的情况下)和动态的(如在drHSC谱系潜力的情况下)。 持久性)。我还将利用我的能力分离三种不同的HSC群体: drHSC、共存的胎儿HSC(fHSC)和成人HSC(aHSC)。这将使我能够问 从独特的视角和新颖的策略,探讨HSC生物学的基本问题: 移植后诱导的drHSC的持久性,而它们的谱系偏好被保留?就是血统 可能仅仅是一种功能丧失现象,或者成体HSC是否具有胎儿HSC 造血干细胞缺乏?如果是,这些是如何获得的?一个HSC群体如何被“重编程”为另一个HSC 亚型?我建议通过评估表观遗传学和转录组动态来研究这些问题(目标1), 以及通过使用CRISPRi小鼠模型功能性地操纵HSC潜能(Aim 2)。由此产生的结果 一项提案将为HSC操作提供基本的概念验证实验, 目的是应用这些工具来提高干细胞移植疗法的疗效。

项目成果

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Atesh K Worthington其他文献

Atesh K Worthington的其他文献

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{{ truncateString('Atesh K Worthington', 18)}}的其他基金

Defining regulators of hematopoietic stem cell self-renewal and lineage potential
定义造血干细胞自我更新和谱系潜力的调节因子
  • 批准号:
    9911115
  • 财政年份:
    2020
  • 资助金额:
    $ 3.83万
  • 项目类别:
Defining regulators of hematopoietic stem cell self-renewal and lineage potential
定义造血干细胞自我更新和谱系潜力的调节因子
  • 批准号:
    10473799
  • 财政年份:
    2020
  • 资助金额:
    $ 3.83万
  • 项目类别:

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