The gut endoderm: origin, formation and fate

肠道内胚层：起源、形成和命运

• 批准号: 10552653
• 负责人: ANNA-KATERINA HADJANTONAKIS
• 金额: $ 65.23万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10552653
• 关键词: Address; Adult; Automobile Driving; Behavior; Binding; Biochemical; Biological Assay; Bladder; Cell Differentiation process; Cell Lineage; Cells; Characteristics; Communication; Development; Disease Progression; Disease model; Ectoderm; Embryo; Embryonic Development; Endoderm; Endoderm Cell; Epiblast; Epithelium; Gastrointestinal tract structure; Genetic; Genetic Transcription; Genomics; Germ Layers; Glean; Goals; Green Fluorescent Proteins; Homeostasis; Image; Image Analysis; Imaging Techniques; Individual; Intestines; Knowledge; Label; Light; Liver; Lung; Mammals; Maps; Mediating; Memory; Mesoderm; Methods; Molecular; Morphogenesis; Movement; Mus; Organ; Organoids; Pancreas; Population; Pregnancy; Process; Reporter; Resolution; Respiratory System; SOX17 gene; Series; Specific qualifier value; Stomach; Technology; Therapeutic; Thymus Gland; Thyroid Gland; Time; Tissues; Tube; Visceral; Visualization; analysis pipeline; body system; cell behavior; cell fate specification; cell type; design; directed differentiation; driving behavior; embryo tissue; fetal; gastrulation; imaging modality; insight; intercalation; mature animal; microscopic imaging; mouse model; novel; novel therapeutic intervention; prospective; public health relevance; rational design; regeneration potential; repaired; screening; tissue regeneration; transcription factor; transcriptomics

PROJECT SUMMARY / ABSTRACT The gut endoderm is the precursor tissue of the respiratory and digestive tracts, and their associated visceral organs. In this project we will use a suite of state-of-the-art technologies to address fundamental questions focused on mechanisms of mammalian gut endoderm cell lineage commitment and tissue morphogenesis, as well as probing the developmental origin and fate of cells that comprise the gut endoderm, using the mouse model. Our previous studies have provided a paradigm-shift in our understanding of the origin and mechanism of formation of the gut endoderm. Using fate mapping, live imaging and more recently single-cell transcriptomic methods, we demonstrated that the gut endoderm of mice comprises cells of two distinct developmental origins; embryonic definitive endoderm, and extra-embryonic visceral endoderm. The dual origin of the gut endoderm challenges the prevailing view of germ layer formation in mammals which posits that endoderm, along with mesoderm and ectoderm, derives solely from pluripotent epiblast. We have also shown that the gut endoderm forms through a novel intercalation mechanism and identified SOX17 as a critical regulator of this process. The broad aim of this project is to use molecular, genomic, embryological and imaging techniques to investigate fundamental open questions pertaining the origin, formation and fate of the gut endoderm in mammals. Specific Aim 1 will investigate the dynamic cellular behaviors driving gut endoderm morphogenesis. Specific Aim 2 will probe the mechanism(s) by which the SOX17 transcription factor drives gut endoderm cell fate specification, tissue morphogenesis and communication between embryonic definitive endoderm and extra-embryonic visceral endoderm cells as they form a congruent epithelium. Specific Aim 3 will determine whether descendants of extra-embryonic visceral endoderm cells persist throughout embryonic development and whether they will ultimately contribute to the endodermal organs of the adult. A rigorous understanding of the normal gut endoderm, encompassing its origin, formation and fate, will underpin logical efforts to direct the differentiation of cells into endoderm identities, generate bona fide endodermal organoids for development and disease modeling and screening, understand disease progression and design new therapeutic strategies for these vital organ systems when they fail.

项目摘要 /摘要 肠道内胚层是呼吸道和消化道的前体组织，它们的内脏 器官。在这个项目中，我们将使用一套最先进的技术来解决基本问题 专注于哺乳动物肠道内胚层细胞谱系的承诺和组织形态发生的机制， 以及探测构成肠内胚层的细胞的发育起源和命运，使用小鼠 模型。 我们以前的研究为我们的理解提供了一种范式迁移 肠内胚层的形成。使用命运映射，实时成像和最近的单细胞转录组 方法，我们证明了小鼠的肠道内胚层包括两个不同发育的细胞 起源；胚胎确定的内胚层和外胚外内胚层。肠的双重起源 内胚层挑战哺乳动物中细菌层形成的普遍视图，这是内胚层的 与中胚层和外胚层一起，仅源自多能层细胞。我们还表明了肠道 内胚层通过一种新型的插入机制形成，并确定SOX17为关键调节剂 这个过程。 该项目的广泛目的是将分子，基因组，胚胎学和成像技术用于 调查与肠内胚层的起源，形成和命运有关的基本开放问题 哺乳动物。特定的目标1将研究驱动肠内胚层的动态细胞行为 形态发生。特定的目标2将探测Sox17转录因子驱动的机制 肠内胚层细胞命运规范，组织形态发生和胚胎确定性之间的通信 内胚层和外胚外内胚层细胞形成一致的上皮。具体目标3 将确定胚外内胚层细胞的后代是否持续在整个胚胎中 发展以及他们是否最终会为成年人的内胚层器官做出贡献。 对正常肠道内胚层的严格理解，包括其起源，形成和命运，将 基础逻辑努力将细胞的分化转化为内胚层身份，产生善意 用于发育和疾病建模和筛查的内胚层类器官，了解疾病进展 并在这些重要器官系统失败时为这些重要器官系统设计新的治疗策略。