Role of Prox1 in Murine Pancreas Development

Prox1 在小鼠胰腺发育中的作用

• 批准号: 6542584
• 负责人: Beatriz Sosa-Pineda
• 金额: $ 29万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6542584
• 关键词: acinar cell; cell cycle; cell growth regulation; cell proliferation; embryo /fetus cell /tissue; gene expression; gene targeting; genetic regulation; genetically modified animals; growth /development; histogenesis; homeobox genes; laboratory mouse; pancreas; protein structure function; transcription factor

DESCRIPTION (provided by applicant): Research on pancreatic cell differentiation and morphogenesis was invigorated by the discovery that many pancreatic disorders arise from defects at different stages of development. The identification of the molecular mechanisms and genetic components that govern pancreas formation has thus turned into a major goal, because these findings should provide tools for better treatment and prevention of pancreatic diseases. Recent studies from my group identified the homeobox-containing gene Prox1 as a novel regulator of mouse pancreas development. Analysis of Prox1-nullizygous embryos suggests that Prox1 regulates pancreatic epithelial-cell proliferation, and that it plays an important role in controlling branching morphogenesis, the expansion of endocrine precursors, and differentiation of exocrine cells. Deciphering the molecular mechanisms whereby Prox1 controls these processes, all of which are absolutely required to form a normal pancreas, should provide us with a novel entry point in helping to understand different aspects of pancreatic organogenesis. The main purpose of this grant proposal is to precisely characterize the functional role of Prox1 in mouse embryonic pancreata by performing a detailed molecular analysis of the pathway(s) regulated by Prox1 in this tissue. To this end I propose the following specific aims: I. To precisely determine the functional role of Prox1 in pancreatic organogenesis, by:A: Revealing proliferation-specific alterations in pancreatic cells of Prox1-nullizygous embryos.B: Determining possible function(s) of Prox1 in pancreatic tissue at later developmental stages.C: Analyzing possible epistasis between Prox1 and Pdx1 in the control of pancreatic growth. II. To identify additional players (epithelial-derived and mesenchymal-derived) participating in thepathway normally regulated by Prox1 during pancreas development, by:A: Determining autonomous and/or non-cell autonomous effects of Prox1 in developing pancreata.B: Identifying soluble and membrane-bound factors participating in this pathway.C: Identifying genes acting downstream of Prox1 during pancreas development. With the proposed studies we expect not only to uncover the molecular pathway(s) regulated by Prox1 during mouse pancreas development, but also to further define important mechanisms involved in mammalian pancreas development and to identify novel genes involved in this process. Our long-term goal is to use this knowledge and the generated molecular markers and mouse mutants to enhance our understanding of pancreas development and pancreatic diseases.

描述(申请人提供)：胰腺细胞分化和形态发生的研究因发现许多胰腺疾病是由不同发育阶段的缺陷引起的而活跃起来的。因此，识别控制胰腺形成的分子机制和遗传成分已成为一个主要目标，因为这些发现应该为更好地治疗和预防胰腺疾病提供工具。 我的团队最近的研究发现，含有同源盒的基因Prox1是小鼠胰腺发育的一种新的调节因子。对Prox1缺合子胚胎的分析表明，Prox1调控胰腺上皮细胞的增殖，并在控制分支形态发生、内分泌前体的扩张和外分泌细胞的分化方面发挥重要作用。破译Prox1控制这些过程的分子机制，所有这些过程都是形成正常胰腺所绝对需要的，应该为我们提供一个新的切入点，帮助我们了解胰腺器官发生的不同方面。这项资助提案的主要目的是通过对Prox1在小鼠胚胎胰腺组织中调控的途径(S)进行详细的分子分析，准确地表征Prox1在该组织中的功能作用。为此，我提出以下具体目标： 为了准确地确定Prox1在胰腺器官发生中的功能作用，通过：A：揭示Prox1零合子胚胎胰腺细胞中增殖特异性的变化；B：确定Prox1在发育后期胰腺组织中的可能功能(S)。C：分析Prox1和Pdx1之间在控制胰腺生长中可能的上位作用。 为了确定更多的参与胰腺发育过程中受Prox1调控的途径的其他成员(上皮来源和间质来源)，方法是：A：确定Prox1在胰腺发育过程中的自主和/或非细胞自主作用；B：识别参与这一途径的可溶性和膜结合因子。C：识别胰腺发育过程中Prox1下游作用的基因。 通过拟议的研究，我们不仅希望揭示Prox1在小鼠胰腺发育过程中调控的分子途径(S)，而且还将进一步确定哺乳动物胰腺发育的重要机制，并识别参与这一过程的新基因。我们的长期目标是利用这些知识以及产生的分子标记和小鼠突变来增强我们对胰腺发育和胰腺疾病的了解。