The role of EMT transcription factor Zeb2 in fetal hematopoiesis

项目摘要 我们的目标是了解红系-髓系祖细胞（EMP）的转录要求 发育和分化成单核细胞和组织驻留巨噬细胞（TRM）。 造血由三个波组成：原始造血、瞬时-永久造血和 永久性造血1 -6。暂时性-永久性和永久性造血需要EMP和造血干细胞。 干细胞（HSC）。EMPs是胚胎发育所必需的，直到造血干细胞接管了胚胎。 初级造血祖细胞和因此缺乏EMP导致妊娠中期死亡7。尽管他们 重要性在胎儿发育，许多仍然是未知的转录要求EMP 发展，部分原因是重叠波之间共享的表面标记和遗传程序， 造血和终末分化谱系。此外，EMP衍生的单核细胞被认为是 成人中大多数TRM人群的主要来源4，8，9。TRM最终在成人中被以下物质取代： 组织特异性速率的HSC衍生单核细胞。EMP-1基因在发育和功能上的差异 衍生的和HSC衍生的TRM以及对组织稳态的影响还没有很好地理解。先前 研究和初步数据表明，转录因子Zeb 2不仅是转录所必需的， TRM身份的维持，但也是EMP形成和/或分化所需的。我们假设 Zeb 2是原始造血祖细胞和瞬时造血干细胞的发育和分化所必需的。 最终的电磁脉冲我们的目的是鉴定新的调控元件和转录因子调节Zeb 2 在原始和瞬时-永久造血过程中表达。 我目前是华盛顿大学圣路易斯医学院的一名医学博士候选人， 有着悠久的历史，支持医生科学家在他们的培训的各个阶段，并正在与一个强大的 致力于指导团队。拟议的培训计划提供新的概念和技术培训，沿着 通过科学，临床和职业发展活动，支持成为独立的 医学科学家，专注于发现造血发育和谱系的机制 分化和应用这些知识推进新的治疗策略。

PROJECT SUMMARY Our goal is to understand the transcriptional requirements for erythroid-myeloid progenitor (EMP) development and differentiation into monocytes and tissue resident macrophages (TRM). Hematopoiesis is comprised of three waves: primitive hematopoiesis, transient-definitive hematopoiesis and definitive hematopoiesis1–6. Transient-definitive and definitive hematopoiesis require EMPs and hematopoietic stem cell (HSCs), respectively. EMPs are required for embryonic development until HSCs take over as the primary hematopoietic progenitors and thus absence of EMPs results in midgestation lethality7. Despite their importance in fetal development, much remains unknown regarding the transcriptional requirements for EMP development, in part due to shared surface markers and genetic programs between overlapping waves of hematopoiesis and terminally differentiated lineages. Additionally, EMP-derived monocytes are recognized as the main source of majority of the TRM populations in adults4,8,9. TRMs are eventually replaced in the adult by HSC-derived monocytes at tissue-specific rates. The developmental and functional differences between EMP- derived and HSC-derived TRM and the impact on tissue homeostasis are not well-understood. Previous studies and preliminary data indicate that the transcriptional factor Zeb2 is not only required for the maintenance of TRM identity but also required for EMP formation and/or differentiation. We hypothesize that Zeb2 is required for the development and differentiation of primitive hematopoietic progenitors and transient- definitive EMPs. We aim to identify novel regulatory elements and transcription factors regulating Zeb2 expression during primitive and transient-definitive hematopoiesis. I am currently a MD-PhD candidate at Washington University in St. Louis School of Medicine, an institution with a long history of supporting physician-scientists at all stages of their training and is working with a strongly committed mentoring team. The proposed training plan provides new conceptual and technical training, along with scientific, clinical, and career development activities that support a trajectory to become an independent physician-scientist focused on discovering mechanisms of hematopoietic development and lineage differentiation and applying this knowledge toward advancing novel therapeutic strategies.