Cellular Decisions of Differentiation in the GI Tract

描述(申请人提供)：目前提交的计划项目拨款(PPG)，“细胞分化的决定在胃肠道”整合了三个研究人员的努力(两个基础科学和一个临床)在密歇根大学的三个部门。拟议研究的中心目标与前两个周期大致相同：(A)了解胃上皮细胞如何通过表达或响应由多肽形态发生原sonic hedgehog(Shh)或跨膜信号受体Notch(B)激活的发育信号通路来发育和维持其特性，以研究胃体、胃窦和肠道中的细胞分化模式如何使用这些信号通路来维持内稳态或对环境应激(例如慢性炎症)做出反应。题为“Hedgehog Signals对髓系细胞表型的调节”的子项目#1将扩展最初的翻译观察，即在髓系细胞中表达的Hedgehog靶基因Glil调节上皮对炎症的反应。题为“Hedgehog信号在慢性胃炎和化生中的作用”的子项目#2将研究慢性炎症，特别是促炎细胞因子在调节细胞分化模式变化中的作用，例如，胃体的化生和胃窦的增生。题为《Notch对胃上皮细胞稳态和肿瘤形成的调控》的子项目#3将探索Notch通路对胃窦部Lgr5干细胞的影响及其与Hedgehog通路的可能相互作用。PPG将支持一个服务核心(细胞生物学核心)，在三个项目之间高效地处理、分析和协调组织样本和流式细胞仪分析。总而言之，PPG将使用各种不同的小鼠模型和基于细胞或分子的方法来了解胃和肠细胞如何维持自身的稳态，但随后改变它们的细胞分化模式，以应对慢性炎症，最终将CLL导向促增殖表型。

DESCRIPTION (provided by applicant): The current submission of the Program Project Grant (PPG), "Cellular Decisions of Differentiation in the Gl Tract" integrates the efforts of three investigators (two basic science and one clinical) from three Departments at the University of Michigan. The central goals of the proposed studies generally remain the same as the prior two cycles: (a) To understand how gastric epithelial cells develop and maintain their identity by expressing or responding to developmental signaling pathways activated by the peptide morphogen sonic hedgehog (Shh) or the transmembrane signaling receptor Notch (b) To investigate how the patterns of cellular differentiation in the gastric corpus, gastric antrum and intestine use these signaling pathways to maintain homeostasis or respond to environmental stress, e.g., chronic inflammation. Subproject #1 entitled "Modulation of myeloid cell phenotype by hedgehog signals" will expand upon the intial translational observation that the Hedgehog target gene Glil expressed in myeloid cells modulates the epithelial response to inflammation. Subproject #2 entitled "Role of Hedgehog signaling in chronic gastritis and metaplasia" will examine the role of chronic inflammation, specifically proinflammatory cytokines in mediating changes in patterns of cellular differentiation, e.g., metaplasia in the gastric corpus and hyperplasia in the antrum. Subproject #3 entitled "Notch Regulation of Gastric Epithelial Cell Homeostasis and Tumorigenesis" will explore the effect of the Notch pathway on Lgr5+ stem cells in the antrum and its possible interaction with the Hedgehog pathway. The PPG will support one service core (Cell Biology Core) to efficiently, process, analyze and coordinate tissue samples and flow cytometric analysis between the three projects. In summary, the PPG will use a variety of different mouse models and cell or molecular -based approaches to understand how gastric and intestinal cells maintain their homeostasis, but then modify their cellular patterns of differentiation in response to chronic inflammation ultimately directing the cll towards a pro-proliferative phenotype.