The gut endoderm: origin, formation and fate

肠道内胚层：起源、形成和命运

• 批准号: 10156809
• 负责人: ANNA-KATERINA HADJANTONAKIS
• 金额: $ 64.88万
• 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/10156809
• 关键词: Address; Adult; Automobile Driving; Behavior; Binding; Biochemical Genetics; Biological Assay; Bladder; Cell Differentiation process; Cell Lineage; Cells; Characteristics; Communication; Development; Disease Progression; Disease model; Ectoderm; Embryo; Embryonic Development; Endoderm; Endoderm Cell; Epiblast; Epithelial; 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; Mediating; Memory; Mesoderm; Methods; Molecular; Morphogenesis; Movement; Mus; Organ; Organoids; Pancreas; Population; Process; Reporter; Resolution; Respiratory System; SOX17 gene; Series; Specific qualifier value; Stomach; Technology; Therapeutic; Thymus Gland; Thyroid Gland; Time; Tissues; Tube; Visceral; analysis pipeline; body system; cell behavior; cell fate specification; cell type; design; driving behavior; embryo tissue; fetal; gastrulation; imaging modality; insight; intercalation; mature animal; microscopic imaging; mouse model; novel; novel therapeutic intervention; prospective; public health relevance; 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.

项目概要/摘要 肠内胚层是呼吸道和消化道及其相关内脏的前体组织 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定型和组织形态发生的机制，如 以及利用小鼠探索构成肠道内胚层的细胞的发育起源和命运 模型。 我们之前的研究为我们理解疾病的起源和机制提供了范式转变。 肠内胚层的形成。使用命运图谱、实时成像和最近的单细胞转录组学 方法，我们证明小鼠的肠道内胚层包含两种不同发育的细胞 起源；胚胎定形内胚层和胚外内脏内胚层。肠道的双重起源 内胚层挑战了哺乳动物胚层形成的普遍观点，该观点认为内胚层， 与中胚层和外胚层一起，仅源自多能外胚层。我们还表明，肠道 内胚层通过一种新颖的嵌入机制形成，并确定 SOX17 是内胚层的关键调节因子 这个过程。 该项目的主要目标是利用分子、基因组、胚胎学和成像技术 研究有关肠道内胚层的起源、形成和命运的基本开放问题 哺乳动物。具体目标 1 将研究驱动肠道内胚层的动态细胞行为 形态发生。具体目标 2 将探究 SOX17 转录因子驱动的机制 肠道内胚层细胞命运规范、组织形态发生和胚胎定形细胞之间的通讯 内胚层和胚外内脏内胚层细胞形成一致的上皮。具体目标 3 将确定胚胎外内脏内胚层细胞的后代是否在整个胚胎时期持续存在 发育以及它们是否最终有助于成人的内胚层器官。 对正常肠道内胚层的严格了解，包括其起源、形成和命运，将有助于 支持引导细胞分化为内胚层特性的逻辑努力，产生真正的 用于发育、疾病建模和筛选的内胚层类器官，了解疾病进展 并在这些重要器官系统出现故障时为它们设计新的治疗策略。