The role of EMT transcription factor Zeb2 in fetal hematopoiesis

项目总结 我们的目标是了解红系祖细胞(EMP)的转录要求。 发育和分化为单核细胞和组织驻留巨噬细胞(TRM)。 造血机分为三波：原始造血波、一过性造血波和终末造血波。 确定的造血1-6.瞬时-确定和确定的造血需要EMPs和造血 干细胞(HSCs)。胚胎发育需要EMPs，直到HSCs取代EMPs 原始造血祖细胞和EMPs的缺乏会导致中期妊娠7。尽管他们 在胎儿发育中的重要性，关于EMP的转录要求仍不清楚 发展，部分是由于在重叠的波之间共享表面标记和遗传程序 造血和终末分化的血统。此外，EMP来源的单核细胞被认为是 成年期大多数TRM种群的主要来源4、8、9。成年后TRM最终被 HSC来源的单核细胞具有组织特异性。电磁脉冲在发育和功能上的差异 衍生和HSC衍生的TRM及其对组织稳态的影响还不是很清楚。上一首 研究和初步数据表明，转录因子ZEB2不仅是 维持TRM特性，但也是EMP形成和/或分化所必需的。我们假设 ZEB2在原始造血祖细胞的发育和分化过程中是必需的，而瞬时的 明确的电磁脉冲。我们的目标是找出调控ZEB2的新的调控元件和转录因子 在原始性和短暂终止性造血过程中表达。 我目前是华盛顿大学圣路易斯医学院的一名医学博士研究生 具有长期支持医生-科学家培训各个阶段的历史，并正在与一个强有力的 忠于职守的指导团队。拟议的培训计划提供新的概念和技术培训，以及 通过科学、临床和职业发展活动支持成为独立的 内科科学家专注于发现造血发育和血统的机制 辨别和应用这些知识来推进新的治疗策略。

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.