The role of Gata 4 in exocrine pancreas development

Gata 4在外分泌胰腺发育中的作用

• 批准号: 6599584
• 负责人: LORI SUSSEL
• 金额: $ 25.92万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6599584
• 关键词: DNA binding protein; acinar cell; antisense nucleic acid; binding sites; cell differentiation; cell growth regulation; embryo /fetus tissue /cell culture; embryogenesis; endoderm; gene expression; gene targeting; genetic promoter element; genetically modified animals; histogenesis; immunocytochemistry; immunoprecipitation; in situ hybridization; laboratory mouse; messenger RNA; pancreas; protein protein interaction; protein structure function; tissue /cell culture; transcription factor

DESCRIPTION (provided by applicant): The ultimate goal of this study is to elucidate the molecular regulation of exocrine pancreas specification and differentiation. Recent advances have been made in understanding how a pancreatic progenitor cell chooses to give rise to an exocrine versus endocrine cell fate. However, once the initial fate decision has been made, the molecular events that control exocrine specification and differentiation are largely unknown. Currently, we are aware of only a single regulatory factor, p48 that is critically required for the generation of differentiated exocrine cells. As in many other developmental systems, the molecular mechanisms that direct the development and differentiation of the exocrine pancreas are likely to involve a complex network of regulatory factors. We have recently determined that Gata4, a zinc-finger transcriptional regulatory factor is expressed in the region of the foregut endoderm that gives rise to pancreas and later becomes restricted to the exocrine acinar cells, where it physically interacts with p48. We hypothesize that Gata4 plays a critical role in the differentiation and development of the exocrine pancreas. To test this hypothesis, we propose to further characterize the expression of Gata4 during embryonic pancreas development and determine its function in the development and differentiation of the exocrine pancreas. The specific aims of this proposal are to: 1. Define the expression pattern of Gata4 in the developing exocrine pancreas. We will determine precisely when and where Gata4 is expressed in the embryonic pancreas and compare its expression patterns to known pancreatic molecular markers. 2. Verify and characterize the physical interaction between Gata4 and p48, an essential exocrine pancreas protein. We will also determine the ability of Gata4 to regulate known exocrine genes that contain Gata and p48 binding sites within in their promoter regions. 3. Identify and characterize the function of Gata4 in exocrine pancreas development. We will use antisense techniques in primary cell cultures and AR42J cells to examine the effects of loss of Gata4 on the development of the exocrine pancreas. 4. Determine the function of Gata4 in exocrine pancreas specification and differentiation in vivo.

描述（由申请人提供）：本研究的最终目标是阐明外分泌胰腺规范和分化的分子调节。最近在理解胰腺祖细胞如何选择产生外分泌细胞与内分泌细胞的命运方面取得了进展。然而，一旦做出了最初的命运决定，控制外分泌规范和分化的分子事件在很大程度上是未知的。目前，我们只知道一个调节因子，p48，它是分化外分泌细胞生成所必需的。与许多其他发育系统一样，指导外分泌胰腺发育和分化的分子机制可能涉及复杂的调节因子网络。我们最近确定，Gata4（一种锌指转录调节因子）在产生胰腺的前肠内胚层区域中表达，随后仅限于外分泌腺泡细胞，在那里它与 p48 发生物理相互作用。我们假设 Gata4 在外分泌胰腺的分化和发育中起着关键作用。为了检验这一假设，我们建议进一步表征胚胎胰腺发育过程中 Gata4 的表达，并确定其在外分泌胰腺发育和分化中的功能。该提案的具体目标是： 1. 定义 Gata4 在发育中的外分泌胰腺中的表达模式。我们将精确确定 Gata4 在胚胎胰腺中表达的时间和位置，并将其表达模式与已知的胰腺分子标记进行比较。 2. 验证并表征 Gata4 和 p48（一种重要的外分泌胰腺蛋白）之间的物理相互作用。我们还将确定 Gata4 调节启动子区域内含有 Gata 和 p48 结合位点的已知外分泌基因的能力。 3. 鉴定并表征 Gata4 在外分泌胰腺发育中的功能。我们将在原代细胞培养物和 AR42J 细胞中使用反义技术来检查 Gata4 缺失对外分泌胰腺发育的影响。 4.确定Gata4在体内外分泌胰腺规范和分化中的功能。