Regulation of pancreatic islet location and size during embryonic development

胚胎发育过程中胰岛位置和大小的调节

• 批准号: 8054338
• 负责人: MARY D KINKEL
• 金额: $ 10.95万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8054338
• 关键词: Beta Cell; Biology; Cell Count; Development; Development Plans; Diabetes Mellitus; Doctor of Philosophy; Embryo; Embryonic Development; Endoderm; Evaluation; Funding; Future; Genes; Germ Layers; Goals; Health; Human; Institution; Islets of Langerhans; Knowledge; Learning; Location; Mentors; Modeling; Mus; Organogenesis; Pancreas; Pattern; Physicians; Positioning Attribute; Primitive foregut structure; Protocols documentation; Publishing; Regulation; Research; Role; Scientist; Secure; Signal Transduction; Stem cells; Structure of beta Cell of islet; Techniques; Testing; Time; Training; Undifferentiated; Work; Zebrafish; base; career; career development; design; in vivo; insight; islet; meetings; mutant; pancreas development; professor; programs; research and development; transcription factor; zebrafish development

DESCRIPTION (provided by applicant): This project is focused on vertebrate pancreas development. I have previously shown that Cdx4 transcription factor is required to limit beta-cell number during development. I have also shown that Cdx4 is required in the endoderm to correctly localize the pancreas. Here I propose to extend that work by further characterizing the role of Cdx4 in pancreas development. I will use zebrafish as an vivo model. Aim 1 will determine the mechanism whereby beta-cell number is limited during early pancreas organogenesis. I will use Cdx4 mutant embryos to test whether beta-cells, or their precursors, have increased proliferation in the absence of Cdx4. This aim will determine the mechanism whereby islet size is limited during normal pancreas development. Aim 2 will test the hypothesis that Wnt signals function upstream of Cdx4 to localize the pancreas. Aim 3 will test the hypothesis that endodermal Hox factors function downstream of Cdx4 to pattern the pre-pancreatic endoderm. Thus, Aims 2 & 3 will identify and characterize factors that function upstream and downstream of Cdx4 during anteroposterior patterning of the pancreatic domain. These aims were designed with the career goal of developing my current research into a more mature research program that will allow me to secure R01 funding in the future, as an independent PI. My immediate goals are to learn new techniques relevant to completing and publishing these aims. My long-term career goals include a commitment to studying pancreas development and function using zebrafish as a model. I plan to secure a tenure-track, full-time Assistant Professor position at an academic institution, where research would be my primary focus. The career development plan includes training via a mentoring committee composed of two developmental biologists, Victoria Prince, PhD and Robert Ho, PhD, both of whom study zebrafish development, and a diabetes physician scientist. Louis Philipson, MD, PhD, who studies mouse and human pancreas biology and diabetes. I will meet regularly with the committee for evaluation of my research and career development progress. PUBLIC HEALTH RELEVANCE: These aims have relevance for stem-cell based diabetes research. Current protocols for directing stem-cells to a beta-cell fate have benefited from insights learned from in vivo developmental studies. The proposed work will extend our current knowledge of how undifferentiated endoderm is patterned to become pancreas, and how beta-cell number is modulated by the embryo.

描述（由申请人提供）： 该项目的重点是脊椎动物胰腺的发展。我以前已经表明，Cdx4转录因子是必需的，以限制β细胞数量在发展过程中。我还表明，Cdx4是内胚层正确定位胰腺所必需的。在这里，我建议通过进一步表征Cdx4在胰腺发育中的作用来扩展这项工作。我将使用斑马鱼作为活体模型。目的1将确定在早期胰腺器官发生过程中β细胞数量受限的机制。我将使用Cdx4突变胚胎来测试β细胞或其前体是否在缺乏Cdx4的情况下增加了增殖。这一目标将确定在正常胰腺发育过程中胰岛大小受限的机制。目的2将检验Wnt信号在Cdx4上游发挥作用以定位胰腺的假设。目的3将检验内胚层Hox因子在Cdx4下游起作用以形成前胰腺内胚层的假设。因此，目的2和3将鉴定和表征在胰腺结构域的前后模式化期间在Cdx4的上游和下游起作用的因子。这些目标的设计与发展我目前的研究成为一个更成熟的研究计划，使我能够在未来获得R01资金的职业目标，作为一个独立的PI。我的近期目标是学习与完成和发布这些目标相关的新技术。我的长期职业目标包括致力于以斑马鱼为模型研究胰腺的发育和功能。我计划在一家学术机构获得一个终身制的全职助理教授职位，在那里研究将是我的主要重点。职业发展计划包括通过由两名发育生物学家维多利亚王子博士和罗伯特何博士组成的指导委员会进行培训，他们都研究斑马鱼发育，以及糖尿病医生科学家。Louis Philipson，医学博士，研究小鼠和人类胰腺生物学和糖尿病。我将定期与委员会会面，评估我的研究和职业发展进展。 公共卫生相关性：这些目标与基于干细胞的糖尿病研究相关。目前用于将干细胞引导至β细胞命运的方案受益于从体内发育研究中获得的见解。这项工作将扩展我们目前对未分化的内胚层如何形成胰腺以及胚胎如何调节β细胞数量的知识。