Investigating the mechanisms of erythroid lineage commitment in hematopoietic stem and multipotent progenitor populations

项目摘要/摘要 阐明谱系指定的潜在机制不仅是生物学的一个基本问题，而且 在治疗目的上也有重要意义。最初的红系血统如何在成人中发生 造血干细胞和多能祖细胞群体在很大程度上没有得到重视，尽管它 有效调节红系细胞产生的潜在临床意义。关于血统偏见的最新发现 在造血干细胞(HSCs)和多能祖细胞(MPP)中提出了一种耐人寻味的可能性，即早期 红系启动发生在HSC和MPP水平。这项提议旨在发现最早的红血球 血统承诺事件及其潜在机制在HSCs和MPP中的研究 和内在因素。首先，我将确定在生成过程中激活的信号通路 用不同的体外和体内方法检测HSCs和MPPS中的红系细胞。第二，内质网的作用 MPP3红系启动中的网状(ER)应激信号将通过分子、细胞和 药理学方法。第三，将研究MPP2中红系启动的表观遗传学调节。 组学分析。这项工作将在伊曼纽尔·帕斯卡博士的实验室进行，在国际上 著名的HSC生物学家，哥伦比亚大学哥伦比亚干细胞计划主任。我的龙- 学期的职业目标是建立我的独立研究计划，构建血统规范网络 血液系统。为了实现这一目标，作为第一步，我将拓宽我的知识基础，并 通过额外的课程/研讨会/会议和实践培训来增加我的技术技能。 为了帮助这一进程，我成立了一个指导和科学咨询委员会，由以下成员组成 具有与我的研究和职业目标相关的不同领域的专业知识的国际知名科学家。 总而言之，拟议的研究将为早期红系血统的机制提供重要的见解。 承诺并提供潜在的新战略来控制红系细胞的生产。此外，这项工作将 为我建立自己独特的研究计划提供了坚实的基础。

PROJECT SUMMARY/ABSTRACT Elucidating the underlying mechanisms of lineage specification is not only a fundamental question of biology but also has a critical implication in therapeutic purpose. How initial erythroid lineage specification occurs in adult hematopoietic stem and multipotent progenitor populations has been largely unappreciated despite of its potential clinical significance to efficiently modulate erythroid cell production. Recent discoveries of lineage bias in hematopoietic stem cells (HSCs) and multipotent progenitors (MPPs) raises an intriguing possibility that early erythroid lineage priming occurs in HSC and MPP levels. This proposal aims to uncover the earliest erythroid lineage commitment events and their underlying mechanisms in HSCs and MPPs by investigating key extrinsic and intrinsic factors. First, I will identify the signaling pathways that are activated during the generation of erythroid cells in HSCs and MPPs using various in vitro and in vivo methods. Second, the role of endoplasmic reticulum (ER) stress signaling in erythroid lineage priming of MPP3 will be tested by molecular, cellular, and pharmacological approaches. Third, epigenetic regulation of erythroid priming in MPP2 will be investigated using omics analysis. This work will be conducted in the laboratory of Dr. Emmanuelle Passegue, internationally renowned HSC biologist and the director of the Columbia Stem Cell Initiative at Columbia University. My long- term career goal is to establish my independent research program constructing lineage specification networks of the blood system. To achieve this goal, as a first step, I will broaden my intellectual knowledge base and increase my technical skill repertoire through additional coursework/workshop/meetings and hands-on training. To aid in this process, I have assembled a mentoring and scientific advisory committee consisting of internationally renowned scientists with expertise in different areas relevant to my research and career goals. Collectively, the proposed studies will provide significant insight into the mechanisms of early erythroid lineage commitment and offer potential new strategies to control erythroid cell production. Moreover, this work will provide me with a solid foundation to establish my unique research program.