Mechanisms regulating hepatic specification and differentiation in zebrafish

斑马鱼肝脏规格和分化的调节机制

基本信息

批准号：
8450191
负责人：
CHONG H SHIN
金额：
$ 11.43万
依托单位：
GEORGIA INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-01 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8450191
关键词：
Adult Affect Animal Model Appearance Bone Morphogenetic Proteins Boxing Cause of Death Cell Lineage Cells Chronic Cicatrix Data Defect Development Differentiation and Growth Duodenum Embryo Embryonic Development Endocrine Endoderm Erinaceidae Exocrine pancreas Fibroblast Growth Factor Foxes Genes Genetic Screening Goals Health Hepatic Homeobox Homeodomain Proteins Injury Intestines Lateral Lead Learning Lesion Liver Liver diseases Malignant neoplasm of liver Microarray Analysis Modeling Molecular Mus Mutagenesis Natural regeneration Neoplasms Organ Pancreas Pattern Positioning Attribute Prevention Primitive foregut structure Principal Investigator Process Regulator Genes Research Proposals Role Series Signal Pathway Signal Transduction Specific qualifier value Stem cells Stomach System Technology Testing Therapeutic Tissues United States Work Zebrafish carcinogenesis cell type chronic liver disease embryo tissue gain of function in vivo insight mutant overexpression prevent progenitor programs regenerative repaired research study response response to injury screening transcription factor

项目摘要

DESCRIPTION (provided by applicant): It has been suggested that the liver and the ventral pancreas originate from common progenitors and share several developmental features. When the liver induction process was prevented in a mouse embryonic tissue explant system by blockig [sic] signals such as Fibroblast growth factors (Fgfs) and Bone morphogenetic proteins (Bmps), the cultured endoderm turned on a gene, Pdx1, that normally expressed in the foregut endoderm [sic], including the stomach, duodenum and pancreas, but not in the liver. Further incubation of these Pdx1 expressing endodermal explants led to the appearance of pancreatic endocrine and exocrine cells, suggesting that the ventral endoderm has the potential to give rise to multiple tissues, including the liver and pancreas. The overall goal of this research proposal is to elucidate mechanisms regulating liver specification and its plasticity, and subsequent differentiation using zebrafish as the main model organism. First, I will investigate how Bmp2b regulates liver versus pancreatic fate decision by performing more detailed lineage tracing analysis ad [sic] loss- and gain-of-function epistatic analysis of Wnt2bb and Bmp2b signaling as well as Hedgehog and Bmp2b signaling. Second, I will investigate how Forkhead box and Homeobox transcription factors function downstream of Bmp2b signaling to regulate liver versus pancreatic fate decision. Expression analysis as well as endoderm-specific loss-and gain-of-function experiments will be performed. Third, I will perform detailed characterization of 4 mutants from large scale mutagenesis screening. They show specific defects in the growth and differentiation of endodermal organs. Once prioritized, identification of the underlying molecular lesion will be followed by extensive analysis, such as expression pattern analysis and loss-and gain-of-function studies. I expect I can answer the fundamental question how the liver and pancreas develop from common progenitors to acquire their unique and overlapping function with series of these experiments.

描述（由申请人提供）：有人认为肝脏和腹侧胰腺起源于共同的祖细胞，并具有一些共同的发育特征。当小鼠胚胎组织外植体系统中的肝脏诱导过程被成纤维细胞生长因子 (Fgfs) 和骨形态发生蛋白 (Bmps) 等信号阻断时，培养的内胚层就会开启一个基因 Pdx1，该基因通常在前肠内胚层[原文如此]，包括胃、十二指肠和胰腺，但不在肝脏中。这些表达 Pdx1 的内胚层外植体的进一步孵育导致胰腺内分泌和外分泌细胞的出现，表明腹侧内胚层有可能产生多种组织，包括肝脏和胰腺。该研究计划的总体目标是阐明调节肝脏规格及其可塑性的机制，以及使用斑马鱼作为主要模式生物的后续分化。首先，我将通过对 Wnt2bb 和 Bmp2b 信号以及 Hedgehog 和 Bmp2b 信号进行更详细的谱系追踪分析和[原文如此]功能丧失和获得上位分析，研究 Bmp2b 如何调节肝脏与胰腺的命运决定。其次，我将研究 Forkhead box 和 Homeobox 转录因子如何在 Bmp2b 信号下游发挥作用，从而调节肝脏与胰腺的命运决定。将进行表达分析以及内胚层特异性功能丧失和获得的实验。第三，我将对大规模诱变筛选中的 4 个突变体进行详细表征。它们在内胚层器官的生长和分化方面表现出特定的缺陷。一旦确定了优先顺序，就会对潜在的分子病变进行识别，然后进行广泛的分析，例如表达模式分析以及功能丧失和获得的研究。我希望我能够通过一系列这些实验来回答肝脏和胰腺如何从共同的祖细胞发育到获得其独特且重叠的功能的基本问题。