Transcriptional Regulators of Exocrine Pancreatic Development

外分泌胰腺发育的转录调节因子

• 批准号: 7797600
• 负责人: RAYMOND J. MACDONALD
• 金额: $ 37.3万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7797600
• 关键词: Acinar Cell; Acinus organ component; Adult; American; Binding; Binding Sites; Biochemical Genetics; Cancer Cell Growth; Cells; Commit; DNA Binding; Data; Derivation procedure; Development; Developmental Gene; Disease; Duct (organ) structure; Ductal Epithelial Cell; Embryo; Embryonic Development; Enhancers; Exocrine pancreas; Gene Expression; Gene Targeting; Genes; Genetic Enhancer Element; Genetic Transcription; Goals; Intercalated Duct; Maintenance; Malignant neoplasm of pancreas; Mediating; Modeling; Molecular Genetics; Multipotent Stem Cells; Natural regeneration; Nature; Nuclear Hormone Receptors; Nuclear Receptors; Organogenesis; Orphan; Pancreas; Pancreatic Bud; Pancreatic carcinoma; Pancreatitis; Pattern; Play; Progress Reports; Property; Regulation; Research; Role; Signal Transduction; Staging; Stem cells; Testing; Time; Transcriptional Activation; Transfection; base; blastomere structure; cell type; genetic analysis; in vivo; islet; neuronal cell body; notch protein; novel marker; precursor cell; progenitor; programs; promoter; public health relevance; therapy development; transcription factor

DESCRIPTION (provided by applicant): The goal of the proposed research is to define the developmental program for the pancreatic acinus. A mature, functional acinus is composed of acinar cells, which surround a specialized form of intercalated duct (the centroacinar cells), and the proximal connecting duct (the intercalated duct). We propose that these three cell-types arise as a single developmental unit from a common progenitor cell-type, the terminal tubule cell of the embryonic pancreas. This model is based on the use of new markers that reveal a developmental intermediate reminiscent of the mature acinus, with gene expression boundaries that suggest discrete developmental compartments with specific functions. To examine this model we will define the roles of two key transcriptional regulators, Ptf1a and Nr5a2, through biochemical and genetic analyses. Ptf1a is expressed in two temporal waves during pancreatic organogenesis: at the onset of pancreatic budding and then at super-induced levels during the secondary transition in multipotent precursor cells and nascent acinar cells, where it appears to control differentiation. We will determine the developmental signals and transcription factors that reactivate the expression of the Ptf1a gene for the beginning of acinar development. We have recently shown that Nr5a2 is required during pancreatic development specifically for the formation of acini and is a direct target of PTF1a. Aim 1 will determine the regulatory mechanisms whereby the nuclear receptor NR5A2 controls the early stage of acinar development. Aim 2 will define the regulatory properties of the transcriptional enhancer that reactivates Ptf1a expression in newly forming acinar cells by identifying DNA-binding transcription factors that mediate the activity of the enhancer and determine which of these factors are required for the regulation of Ptf1a expression during embryogenesis and for normal acinar development. Aim 3 will determine the manner in which Wnt and Notch developmental signal are integrated into transcriptional activation of the Ptf1a gene during embryonic development. PUBLIC HEALTH RELEVANCE: Pancreatitis and pancreatic cancer are common diseases of the pancreas. By understanding the control of normal development of the exocrine pancreas we hope to contribute to therapies that may help a pancreas badly damaged by pancreatitis to regenerate, or to identify ways to stop the growth of cancer cells derived from the exocrine pancreas without damaging other cells of the body.

描述（由申请人提供）：拟议研究的目的是定义胰腺刺激的发展计划。成熟的功能性刺激性由腺泡细胞组成，腺泡细胞围绕着插入的导管（质心细胞）和近端连接导管（嵌入导管）的特殊形式。我们建议，这三种细胞类型是由公共祖细胞型（胚胎胰腺的末端小管细胞）的单个发育单元出现的。该模型基于使用新标记的使用，这些新标记揭示了发育中间的让人联想到成熟的acinus，其基因表达边界表明具有特定功能的离散发育室。为了检查该模型，我们将通过生化和遗传分析来定义两个关键的转录调节剂PTF1A和NR5A2的作用。 PTF1A在胰腺器官发生过程中以两个时间波的形式表达：在胰腺发芽时，然后在多能前体细胞和新生腺泡细胞中的二次过渡期间在超级诱导的水平上表达。我们将确定在腺泡发育开始的PTF1A基因表达的重新激活的发育信号和转录因子。我们最近表明，在胰腺开发过程中需要专门为acini形成而需要NR5A2，并且是PTF1A的直接靶标。 AIM 1将确定核受体NR5A2控制腺泡发育的早期阶段的调节机制。 AIM 2将通过鉴定介导增强子活性的DNA结合转录因子来定义转录增强子的调节特性，该转录增强子的调节性能将新形成腺泡细胞中的PTF1A表达重新激活，并确定这些因素中的哪些因素在胚胎发生和正常腺泡发育过程中需要调节PTF1A表达。 AIM 3将确定Wnt和Notch发育信号在胚胎发育过程中将Wnt和Notch发育信号整合到PTF1A基因的转录激活的方式。 公共卫生相关性：胰腺炎和胰腺癌是胰腺的常见疾病。通过了解对外分泌胰腺正常发育的控制，我们希望为疗法做出贡献，这些疗法可能有助于胰腺炎严重损害的胰腺再生，或者确定停止从外分泌胰腺造成的癌细胞生长而无需损害身体其他细胞的方法。