Morphogenesis of mammalian gut endoderm

哺乳动物肠道内胚层的形态发生

• 批准号: 8761206
• 负责人: ANNA-KATERINA HADJANTONAKIS
• 金额: $ 51.74万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8761206
• 关键词: Address; Adult; Automobile Driving; Behavior; Biology; Bladder; Cell Differentiation process; Cell Lineage; Cell Therapy; Cells; Defect; Development; Disease; Disease Progression; Disease model; Ectoderm; Embryo; Embryonic Development; Embryonic Structures; Endoderm; Endoderm Cell; Epiblast; Epithelial Cells; Event; Exhibits; Fetal Tissues; Gastrointestinal tract structure; Gastrula; Genetic; Germ Layers; Green Fluorescent Proteins; Image; Image Analysis; Imaging Techniques; In Vitro; Intestines; Knowledge; Label; Life; Light; Liver; Lung; Mammals; Maps; Mesoderm; Modeling; Molecular; Morphogenesis; Mus; Mutant Strains Mice; Organ; Pancreas; Placenta; Population; Process; Protocols documentation; Reporter; Respiratory System; Respiratory tract structure; Role; Signal Transduction; Staging; Stomach; Structure; Technology; Testing; Thymus Gland; Thyroid Gland; Tissues; Tube; Visceral; Yolk Sac; base; biliary tract; blastocyst; blastomere structure; body system; cell behavior; cell type; design; embryo tissue; gastrulation; implantation; intercalation; mutant; novel; novel therapeutics; public health relevance; segregation; stem cell differentiation

DESCRIPTION (provided by applicant): In this project we will use state-of-the-art technologies to address fundamental questions of cell lineage commitment, segregation and morphogenesis in mammals, using the mouse as a model. This proposal focuses on the gut endoderm, an embryonic tissue that gives rise to the major cell types of many internal organs, including the thyroid, thymus, lung, stomach, liver, pancreas, intestine and bladder. A rigorous understanding of normal gut endoderm morphogenesis, including knowledge of the origin, commitment, specification and differentiation of cells generating gut endoderm and its derivative tissues, should underpin logical efforts to understand disease progression and design new therapeutic strategies for these vital organ systems. The prevailing view of germ layer formation in mammalian embryos is that the gut endoderm, along with the ectoderm and mesoderm, derives solely from the pluripotent epiblast during the process of gastrulation. Moreover, while extra-embryonic tissues interact with the epiblast to establish the body axes, they contribute solely to extra-embryonic structures, such as the yolk sac and placenta. Our studies challenge this view, and inform the hypotheses being tested in the Specific Aims of this project. The broad aim of this project is to use a combination of molecular, embryological and live imaging techniques to determine the fate of the visceral endoderm a presumed extra-embryonic tissue, and investigate its role(s) in the morphogenesis of the mammalian gut endoderm. In Specific Aim 1, we will determine if a lineage relationship exists between the visceral endoderm and the gut endoderm tissues of the fetus and adult mouse. In Specific Aim 2, we will elucidate the mechanisms that drive gut endoderm morphogenesis. Specific Aim 3, investigates the sequence of events leading to the organization of extra-embryonic (visceral) endoderm cells around midline signaling centers, and test the hypothesis that this arrangement is central to midline formation and/or function. Our findings are also relevant to stem cell differentiation for cell-based therapies and disease modeling because, current protocols for the in vitro differentiation of liver lung, pancreas and other endodermal cell types assume an epiblast-only origin and specifically select against the extra-embryonic endoderm that forms prior to gastrulation.

描述（由申请人提供）：在此项目中，我们将使用最先进的技术来解决哺乳动物中细胞谱系承诺，隔离和形态发生的基本问题，并使用鼠标作为模型。该提案的重点是肠道内胚层，肠道内胚层是一种胚胎组织，引起许多内部器官的主要细胞类型，包括甲状腺，胸腺，肺，肺，胃，肝脏，肝脏，胰腺，肠，肠和膀胱。对正常肠道内胚层形态发生的严格理解，包括对产生肠道内胚层及其衍生物组织的细胞的承诺，规范和分化的了解，应支持逻辑上的逻辑努力，以了解这些重要器官系统的疾病进展并设计新的治疗策略。 哺乳动物胚胎中生殖层形成的普遍视图是，肠内胚层与外胚层和中胚层一起仅源自胃胃过程中多能层层。此外，虽然外胚型组织与层细胞相互作用以建立身体轴，但它们仅促进外胚型结构，例如蛋黄囊和胎盘。我们的研究挑战了这一观点，并告知在该项目的具体目的中测试的假设。 该项目的广泛目的是结合分子，胚胎学和活成像技术来确定内脏内胚层假定的外胚外组织的命运，并研究其在哺乳动物肠道内胚二甲体形成中的作用。在特定的目标1中，我们将确定内胚层和胎儿和成年小鼠的肠内内胚层组织之间是否存在谱系关系。在特定的目标2中，我们将阐明驱动肠道内胚层形态发生的机制。具体目标3，研究了导致在中线信号中心周围组织外胚（内脏）内胚层细胞组织的事件序列，并测试了这种布置是中线形成和/或功能的核心的假设。 我们的发现也与基于细胞的疗法和疾病建模的干细胞分化有关，因为当前的肝脏肺，胰腺和其他内胚层细胞类型的体外分化方案假设仅具有层生细胞的起源，并针对外胚型内胚层特定选择。