Cellular Decisions of Differentiation in the GI Tract

项目描述（由申请人提供）：项目项目资助（PPG），“Gl Tract分化的细胞决定”整合了密歇根大学医学院三个系的三位研究者（一位基础科学和两位临床）的努力。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因子sonic hedgehog （Shh）来发育和维持其特性(b)研究胃分泌酸上皮细胞分化模式如何响应病理性损伤，例如炎症（这种损伤可以改变胃上皮的特性，使其获得小肠表型）。子课题1题为“胃祖细胞亚群的生物学”，将研究胃祖细胞（干细胞）在胚胎发育的时间进程及其对Shh或促炎细胞因子干扰素的反应。子项目#2题为“胃内稳态和病理中的刺猬信号”，将使用LacZ报告小鼠来识别和表征表达和响应刺猬信号的胃细胞群。此外，还将分析hedgehog信号如何介导上皮-间质串扰。子项目#3题为“壁细胞刺猬的作用是正常的和发炎的胃”，将重点研究壁细胞如何产生具有生物活性的Shh并介导体-心房串扰。所有项目的重点是解剖胃的发育途径，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研究人员-细胞生物学（核心A）和行政（核心B）。细胞生物学核心将使用最先进的成像和生物信息学技术促进小鼠模型的分析。行政核心将通过每月组织联合会议和共同邀请发言者，加强这三名调查人员在各部门之间已经很密切的互动。这将进一步加深我们对胃细胞如何决定身份和分化的理解，并为与公共卫生相关的炎症信号如何改变其表型提供线索。

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.