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

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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.