Transcriptional Regulators of Exocrine Pancreatic Development

描述（由申请方提供）：拟定研究的目的是确定胰腺腺泡的发育程序。一个成熟的、有功能的腺泡由腺泡细胞组成，腺泡细胞围绕着一个特殊形式的闰管（中心腺泡细胞）和近端连接管（闰管）。我们认为，这三种细胞类型作为一个单一的发展单位，从一个共同的祖细胞类型，终末小管细胞的胚胎胰腺。这个模型是基于使用新的标记，揭示了一个发展中间让人想起成熟的腺泡，与基因表达的边界，建议离散的发展车厢具有特定的功能。为了检验这个模型，我们将通过生化和遗传分析来定义两个关键转录调节因子Ptf 1a和Nr 5a2的作用。Ptf1a在胰腺器官发生过程中以两种时间波表达：胰腺出芽开始时，然后在多能前体细胞和新生腺泡细胞的次级转变期间以超诱导水平表达，在那里它似乎控制分化。我们将确定重新激活Ptf1a基因表达的发育信号和转录因子，以开始腺泡发育。我们最近表明，Nr 5a 2是胰腺发育过程中所需的，特别是腺泡的形成，并且是PTF 1a的直接靶点。目的1将确定核受体NR5A2控制早期腺泡发育的调控机制。目的2将定义的转录增强子，重新激活Ptf1a在新形成的腺泡细胞中的表达的调节特性，通过识别DNA结合转录因子介导的增强子的活性，并确定这些因子中的哪些是需要在胚胎发育和正常腺泡发育过程中的Ptf1a的表达的调节。目的3将确定Wnt和Notch发育信号在胚胎发育过程中整合到Ptf1a基因的转录激活中的方式。 胰腺炎和胰腺癌是胰腺的常见疾病。通过了解外分泌胰腺正常发育的控制，我们希望有助于治疗，可能有助于胰腺炎严重受损的胰腺再生，或确定方法来阻止来自外分泌胰腺的癌细胞的生长，而不损害身体的其他细胞。

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.