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

项目概要/摘要 阐明谱系特化的潜在机制不仅是生物学的基本问题， 在治疗目的上也有重要意义。在成人中如何发生初始红系谱系特化 造血干细胞和多能祖细胞群体尽管具有 有效调节红系细胞产生的潜在临床意义。血统偏见的最新发现 在造血干细胞（HSC）和多能祖细胞（MPPs）中， 在HSC和MPP水平上发生红系谱系引发。这项提案旨在揭示最早的红细胞 造血干细胞和MPP的谱系承诺事件及其潜在机制，通过研究关键的外在 和内在因素。首先，我将识别在产生细胞周期中激活的信号通路。 使用各种体外和体内方法在HSC和MPP中检测红系细胞。二、内质的作用 将通过分子、细胞和免疫组织化学方法测试MPP 3的红系引发中的内质网（ER）应激信号传导。 药理学方法。第三，将使用以下方法研究MPP 2中红系引发的表观遗传调节： 组学分析这项工作将在Emmanuelle Passegue博士的实验室进行， 著名的HSC生物学家和哥伦比亚大学哥伦比亚干细胞计划主任。我的长- 我的职业目标是建立我的独立研究项目，构建谱系规范网络 的血液系统。为了实现这个目标，作为第一步，我将扩大我的知识基础， 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，我组建了一个指导和科学咨询委员会， 国际知名的科学家，在与我的研究和职业目标相关的不同领域拥有专业知识。 总的来说，拟议的研究将为早期红系细胞谱系的机制提供重要的见解。 并提供潜在的新策略来控制红系细胞的产生。此外，这项工作将 为我提供了一个坚实的基础，以建立我独特的研究计划。

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.