Role of Prox1 in Murine Pancreas Development

Prox1 在小鼠胰腺发育中的作用

• 批准号: 6607258
• 负责人: Beatriz Sosa-Pineda
• 金额: $ 26.25万
• 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 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6607258
• 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）：许多胰腺疾病是由不同发育阶段的缺陷引起的，这一发现激发了对胰腺细胞分化和形态发生的研究。因此，确定控制胰腺形成的分子机制和遗传成分已经成为一个主要目标，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。