Cellular Decisions of Differentiation in the GI Tract

描述（由申请人提供）： 计划项目资助（PPG）“GI道分化的细胞决定”整合了来自密歇根大学医学院三个系的三名研究人员（一名基础科学和两名临床）的努力。所提出的研究的中心目标是：（a）了解胃上皮细胞如何通过表达或响应肽形态原sonic hedgehog（Shh）来发育和维持其身份（B）研究胃的酸分泌上皮中的细胞分化模式如何响应病理性损伤而改变，例如，炎症（这种损伤可以改变胃上皮的特性，使得其获得小肠表型）。子项目1题为“胃祖细胞亚群的生物学”，将研究胚胎中胃祖（干）细胞发育的时间过程及其对Shh或促炎细胞因子干扰素γ的反应。子项目#2题为“胃稳态和病理学中的刺猬信号”，将使用LacZ报告小鼠来鉴定和表征表达和响应刺猬信号的胃细胞群。此外，刺猬信号如何介导的上皮间充质串扰将进行分析。子项目#3题为“壁细胞刺猬的作用是正常的和发炎的胃，”将集中在生物活性嘘是如何产生的壁细胞和介导的小体胃窦串扰。所有项目都专注于解剖胃中的发育途径，并广泛使用小鼠模型来询问主要与Shh相关的重要信号通路。两个核心将协助PPG验证员-细胞生物学（核心A）和管理（核心B）。细胞生物学核心将有助于使用最先进的成像和生物信息学技术分析小鼠模型。行政核心将通过组织每月联席会议和共同赞助特邀发言人，加强这三名调查员之间跨部门的强有力互动。这将进一步加深我们对胃细胞如何做出身份和分化决定的理解，并提供有关炎症信号如何改变其表型的线索。

DESCRIPTION (provided by applicant): The Program Project Grant (PPG), "Cellular Decisions of Differentiation in the Gl Tract" integrates the efforts of three investigators (one basic science and two clinical) from three Departments at the University of Michigan Medical School. The central goals of the proposed studies are: (a) To understand how gastric epithelial cells develop and maintain their identity by expressing or responding to the peptide morphogen sonic hedgehog (Shh) (b) To investigate how the patterns of cellular differentiation in the acid-secreting epithelium of the stomach changes in response to pathological insults, e.g., inflammation (such insults can alter the identity of the gastric epithelium, such that it acquires a small intestinal phenotype). Subproject 1 entitled "Biology of a Sub-population of Gastric Progenitor Cells" will examine the time course of gastric progenitor (stem) cell development in the embryo and their response to Shh or the proinflammatory cytokine interferon gamma. Subproject #2 entitled, "Hedgehog signaling in stomach homeostasis and pathology," will use LacZ reporter mice to identify and characterize the gastric cell populations that express and respond to hedgehog signals. In addition, how hedgehog signals mediate the epithelial-mesenchymal crosstalk will be analyzed. Subproject #3 entitled "Role of Parietal Cell Hedgehog is normal and Inflamed Stomach," will focus on how biologically active Shh is generated from the parietal cell and mediates corpus-antral crosstalk. All projects focus on dissecting developmental pathways in the stomach and make extensive use of mouse models to interrogate important signaling pathways primarily related to Shh. Two Cores will assist the PPG investigators-the Cell Biology (Core A) and the Administrative (Core B). The Cell Biology Core will facilitate the analysis of the mouse models using state-of-the-art imaging and bioinformatics techniques. The Administrative Core will enhance the already strong interaction between these three investigators across department lines by organizing monthly joint meetings and co-sponsoring invited speakers. This will further our understanding of how gastric cells make decisions of identity and differentiation and provide clues on how their phenotype is altered by inflammatory signals as relevant to public health.