Mammalian Foregut and Liver Development

哺乳动物前肠和肝脏发育

• 批准号: 7582986
• 负责人: James M Wells
• 金额: $ 39.44万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7582986
• 关键词: Anterior; Bile fluid; Blood Proteins; Cardiac; Cell Adhesion; Cell Culture Techniques; Cells; Data; Defect; Development; Disease; Dose; Drug Metabolic Detoxication; Embryo; Embryonic Development; Endocrine; Endoderm; Event; Exhibits; Exocrine Glands; Fibroblast Growth Factor; Gastrula; Gene Expression; Generations; Genetic; Genetic Programming; Glucose; Glycogen; Goals; Hepatic; Hepatocyte; Hindgut; Human; In Vitro; Intestines; Knock-out; Knowledge; Lateral; Life; Ligands; Link; Liver; Liver diseases; Mammals; Mediating; Mesoderm; Methods; Modeling; Molecular; Morphogenesis; Mus; Operating System; Organ; Pathway interactions; Pattern; Phenotype; Primitive foregut structure; Publishing; Reporting; Repression; Research; Role; Signal Transduction; Site; Somites; Source; Staging; Testing; Time; Tissue Transplantation; Tissues; Translating; Undifferentiated; Xenopus; beta catenin; cell type; embryonic stem cell; human disease; human embryonic stem cell; insight; liver transplantation; monolayer; mutant; progenitor; public health relevance; receptor; research study; response

DESCRIPTION (provided by applicant): The long-term goal of this proposal is to elucidate the molecular mechanism controlling mammalian foregut and early liver development. The largest exocrine gland in the body the liver produces bile and is the primary site for detoxification. It also performs important endocrine functions by secreting homeostatic blood proteins and regulating glucose levels through glycogen storage. A recent trans-NIH report "Action Plan for Liver Disease Research (2004)" recognized that a better understanding of embryonic liver development would provide important insights into human liver disease and promote our ability to harness embryonic stem cells as a renewable source of tissue for transplantation. The mouse embryonic liver is induced from the ventral foregut endoderm by FGF signals from the cardiac mesoderm. While we increasingly understand the genetic pathways regulating proliferation and differentiation of hepatoblasts after the liver bud has formed, the earlier events linking endoderm patterning to hepatic specification are less clear. In Xenopus we recently determined that differential Wnt/beta-catenin signaling regulates endoderm fates. Our data supports a model where during gastrula and early somite stages secreted Wnt- antagonists in the anterior endoderm establish foregut identity and initiate a molecular cascade leading to liver development. In contrast, the posterior endoderm has high beta-catenin activity, due to Wnt ligands secreted from the lateral/axial mesoderm, which represses foregut fate and promotes intestinal development. We propose to test this hypothesis using mouse genetics and embryonic explants to characterize the underlying molecular mechanism. Moreover, we will investigate whether analogous pathways are important for liver development in humans using endoderm cultures derived from human embryonic stem cells. The results of this proposal will directly impact efforts to generate therapeutically useful endoderm tissue for the treatment of liver disease in humans. Aim 1. Determine if repression of beta-catenin activity in the anterior endoderm is required for foregut and liver development using mouse genetics. Aim 2. Define when beta-catenin needs to be repressed and examine how the temporally distinct Wnt and FGF pathways interact during hepatic development, using mouse embryonic explant cultures. Aim 3. Investigate the role of Wnt signaling in promoting human foregut and liver lineages from HESCs. PUBLIC HEALTH RELEVANCE. The liver is a vital organ providing many essential functions and numerous diseases are so life threatening that liver transplantation is the only option. The differentiation of liver cells from embryonic stem cells is a potentially renewable source of tissue for transplantation. The goal of this proposal is to elucidate the genetic programs controlling embryonic liver development in mice. We will then use this information to recapitulating the key embryonic events in human embryonic stem cells to more effectively generate liver tissue in culture.

描述（由申请人提供）：该提案的长期目标是阐明控制哺乳动物前肠和早期肝脏发育的分子机制。肝脏是体内最大的外分泌腺，产生胆汁，是解毒的主要场所。它还通过分泌稳态血液蛋白和通过糖原储存调节血糖水平来执行重要的内分泌功能。最近的跨国家卫生研究院报告“肝病研究行动计划（2004）”认识到，更好地了解胚胎肝发育将为了解人类肝病提供重要见解，并提高我们利用胚胎干细胞作为移植组织的可再生来源的能力。小鼠胚胎肝脏是由心脏中胚层的 FGF 信号从腹侧前肠内胚层诱导而来。虽然我们越来越了解肝芽形成后调节成肝细胞增殖和分化的遗传途径，但将内胚层模式与肝脏规格联系起来的早期事件尚不清楚。在非洲爪蟾中，我们最近确定差异性 Wnt/β-连环蛋白信号传导调节内胚层命运。我们的数据支持这样一个模型：在原肠胚和早期体节阶段，前内胚层中分泌的Wnt拮抗剂建立前肠身份并启动导致肝脏发育的分子级联反应。相反，由于侧/轴中胚层分泌的 Wnt 配体，后内胚层具有高 β-连环蛋白活性，抑制前肠命运并促进肠道发育。我们建议使用小鼠遗传学和胚胎外植体来测试这一假设，以表征潜在的分子机制。此外，我们将使用源自人类胚胎干细胞的内胚层培养物来研究类似的途径对于人类肝脏发育是否重要。该提案的结果将直接影响生成治疗有用的内胚层组织以治疗人类肝病的努力。目标 1. 使用小鼠遗传学确定前内胚层中 β-连环蛋白活性的抑制对于前肠和肝脏发育是否是必需的。目标 2. 使用小鼠胚胎外植体培养物确定何时需要抑制 β-连环蛋白，并检查肝发育过程中时间上不同的 Wnt 和 FGF 通路如何相互作用。目标 3. 研究 Wnt 信号传导在促进 HESC 人类前肠和肝谱系中的作用。公共卫生相关性。 肝脏是一个重要的器官，提供许多基本功能，许多疾病危及生命，肝移植是唯一的选择。肝细胞从胚胎干细胞的分化是移植组织的潜在可再生来源。该提案的目的是阐明控制小鼠胚胎肝脏发育的遗传程序。然后，我们将利用这些信息来概括人类胚胎干细胞的关键胚胎事件，以更有效地在培养物中产生肝组织。