The role of EMT transcription factor Zeb2 in fetal hematopoiesis

EMT转录因子Zeb2在胎儿造血中的作用

• 批准号: 10604587
• 负责人: Jing Chen
• 金额: $ 3.36万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10604587
• 关键词: ATAC-seq; Address; Adult; Alleles; Binding; Binding Sites; Biological Assay; Brain; Chromatin; Clustered Regularly Interspaced Short Palindromic Repeats; Data; Defect; Development; Disease; Doctor of Philosophy; Embryo; Embryonic Development; Endothelium; Enhancers; Erythrocytes; Erythroid; Erythropoiesis; Exhibits; Fetal Development; Fetal Liver; Fetus; Flow Cytometry; Genetic; Genetic Enhancer Element; Genetic Transcription; Goals; Harvest; Health; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Hepatocyte; Heterogeneity; Homeobox; Homeostasis; In Vitro; Infection; Institution; Knockout Mice; Knowledge; LoxP-flanked allele; Macrophage; Maintenance; Megakaryocytes; Mentors; Methylcellulose; Microglia; Mus; Mutagenesis; Myelogenous; Phenotype; Physicians; Population; Pregnancy; Recording of previous events; Regulatory Element; Reporter; Retroviridae; Role; Scientist; Site; Sorting; Source; Stem Cell Factor; Surface; System; Technology; Tissues; Training; Transcriptional Regulation; Transgenic Organisms; Travel; Universities; Washington; Yolk Sac; Zinc Fingers; career development; clinical development; erythroid differentiation; experience; fetal; histone modification; in vivo; medical schools; monocyte; mouse model; next generation sequencing; novel; novel therapeutic intervention; progenitor; programs; single-cell RNA sequencing; stem cell derived tissues; transcription factor; vector

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.

项目摘要 我们的目标是了解红细胞乳突祖细胞（EMP）的转录要求 开发和分化为单核细胞和组织居民巨噬细胞（TRM）。 造血的三波完成：原始造血，瞬态定义造血和 确定的造血1-6。瞬态定义和确定的造血需要EMP和造血 干细胞（HSC）分别。胚胎开发需要EMP，直到HSC接管 原发性造血祖细胞，因此缺乏EMP会导致中间质量杀伤力7。尽管他们 在胎儿发育中的重要性，在EMP的转录要求上仍然未知 开发，部分是由于共享的表面标记和重叠波之间的遗传程序 造血和最终分化的谱系。此外，EMP衍生的单核细胞被认为是 大多数成人TRM人群的主要来源为4,8,9。有时在成人中替换了TRM HSC衍生的单核细胞以组织特异性速率。 EMP- 衍生和HSC衍生的TRM以及对组织稳态的影响并不理解。以前的 研究和初步数据表明，转录因子Zeb2不仅需要 维护TRM身份，但也需要EMP形成和/或分化。我们假设这一点 Zeb2是原始造血祖细胞和瞬态的发展和分化所必需的 确定的EMP。我们旨在确定调节Zeb2的新型调节元件和转录因子 在原始和瞬态定义的造血中的表达。 我目前是圣路易斯医学院华盛顿大学的MD-PHD候选人，一家机构 在培训的各个阶段都支持身体科学家的历史悠久，并且正在与之合作 承诺的指导团队。拟议的培训计划提供了新的概念和技术培训 通过科学，临床和职业发展活动，支持轨迹成为独立的轨迹 身体科学家的重点是发现造血发展和谱系的机制 分化并将这些知识应用于推进新型治疗策略。