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: 7782782
• 负责人: MARY D KINKEL
• 金额: $ 10.71万
• 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 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7782782
• 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; 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; public health relevance; 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育。我之前已经证明，在发育过程中需要 Cdx4 转录因子来限制 β 细胞数量。我还表明，内胚层需要 Cdx4 才能正确定位胰腺。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体内模型。目标 1 将确定早期胰腺器官发生过程中 β 细胞数量受到限制的机制。我将使用 Cdx4 突变胚胎来测试 β 细胞或其前体在没有 Cdx4 的情况下是否会增加增殖。这一目标将确定正常胰腺发育过程中胰岛大小受到限制的机制。目标 2 将检验 Wnt 信号在 Cdx4 上游发挥作用以定位胰腺的假设。目标 3 将检验内胚层 Hox 因子在 Cdx4 下游发挥作用以形成胰腺前内胚层的假设。因此，目标 2 和 3 将识别和表征在胰腺结构域的前后模式过程中在 Cdx4 上游和下游发挥作用的因素。这些目标是为了将我当前的研究发展为更成熟的研究项目而设计的，这将使我能够在未来作为独立 PI 获得 R01 资助。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终身教授的全职助理教授职位，研究将是我的主要关注点。职业发展计划包括通过由两名发育生物学家维多利亚·普林斯博士和罗伯特·何博士（两人都研究斑马鱼发育）和一名糖尿病医师科学家组成的指导委员会进行培训。 Louis Philipson，医学博士、哲学博士，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。 公共健康相关性：这些目标与基于干细胞的糖尿病研究相关。目前用于引导干细胞走向β细胞命运的方案受益于从体内发育研究中获得的见解。拟议的工作将扩展我们目前对未分化内胚层如何形成胰腺以及胚胎如何调节β细胞数量的了解。