Mechanisms regulating hepatic specification and differentiation in zebrafish

斑马鱼肝脏规格和分化的调节机制

• 批准号: 7660630
• 负责人: CHONG H SHIN
• 金额: $ 8.94万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 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/7660630
• 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; 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; Screening procedure; Series; Signal Pathway; Signal Transduction; Specific qualifier value; Stem cells; Stomach; System; Technology; Testing; Therapeutic; Tissues; United States; Work; Zebrafish; carcinogenesis; cell type; embryo tissue; gain of function; in vivo; insight; mutant; overexpression; prevent; progenitor; programs; public health relevance; regenerative; repaired; research study; response; response to injury; transcription factor

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. PUBLIC HEALTH RELEVANCE: Liver disease is a major cause of death in the United States and world wide. In general it reflects a chronic response to injury, in which repair and regeneration lead to scarring and/or neoplasia. Often, repair and regeneration in the adult recapitulate embryonic development. Thus, understanding the mechanisms of development has direct implications for prevention and treatment of chronic injury and liver cancer.

描述（由申请人提供）： 有人提出，肝脏和腹胰腺起源于普通祖细胞，并具有多种发育特征。当通过块状[SIC]信号（例如成纤维细胞生长因子（FGFS）和骨形态发生蛋白（BMP））在小鼠胚胎组织外植体系统中预防肝诱导过程时，经培养的内胚层在基因，PDX1上打开的PDX1，PDX1，通常在Foregut Endoderm insiC Indoderm [SIC]（包括SIC）（包括SIC [SIC] LOUDES，DUODENUM和DUODENUM PUDODEN，DUODENEN和DUODENIUM duodeNum and Duoden and p. duoden and duoden and duoden and duoden and duoden and p.这些表达内胚层外植体的这些PDX1进一步孵育导致胰腺内分泌和外分泌细胞的出现，这表明腹侧内胚层有可能引起多种组织，包括肝脏和胰腺。该研究建议的总体目标是阐明调节肝脏规范及其可塑性的机制，以及随后使用斑马鱼作为主要模型生物的分化。首先，我将研究BMP2B如何通过执行更详细的谱系跟踪分析来调节肝脏与胰腺命运的决策。其次，我将调查BMP2B信号传导下游的分叉盒和同源转录因子如何调节肝脏与胰腺命运决策。将进行表达分析以及内胚层特异性损失和功能获得实验。第三，我将对大规模诱变筛选的4个突变体进行详细表征。它们在内皮器官的生长和分化中表现出特定的缺陷。一旦优先考虑，对基本分子病变的识别将进行广泛的分析，例如表达模式分析以及丧失和功能获得的研究。我希望我可以回答一个基本问题，肝脏和胰腺如何从共同的祖细胞中发展起来，通过一系列这些实验获得其独特而重叠的功能。 公共卫生相关性：肝病是美国和全球的主要死亡原因。通常，它反映了对损伤的长期反应，其中修复和再生会导致疤痕和/或肿瘤。通常，成人概括的胚胎发育中的修复和再生。因此，了解发展机制对预防和治疗慢性损伤和肝癌具有直接影响。