Cellular Decisions of Differentiation in the GI Tract

描述(由申请人提供)： 项目资助(PPG)“胃肠道分化的细胞决定”整合了来自密歇根大学医学院三个系的四名研究人员(两名基础科学和两名临床)的努力。PPG提出的这项工作的中心目标是：(A)了解上消化道的上皮细胞如何在个体发育期间获得组织同一性(胃与小肠)和谱系同一性(肠内分泌细胞与肠细胞或杯状细胞)；(B)研究胃分泌酸性上皮的细胞分化模式通常是如何通过特定的细胞内途径控制的，以及这些途径是如何被病理侮辱(这种侮辱可导致胃上皮的特性改变，从而获得小肠表型)的。子项目#1从组织特定的角度(胃与肠)、区域角度(十二指肠与远端肠)和分化角度(隐窝与末端)，研究控制肠道上皮细胞同一性的顺式和反式因子。此外，与子项目#2和#4一起，将研究当胃细胞在病理性侮辱后获得肠道特性(肠化生)时基因调控如何变化的问题。子项目2将使用CCK作为该细胞室的早期标记物，追踪肠道内肠内分泌细胞谱系的发展。这项工作将利用在子项目#1中产生的调节性转基因。子项目#3将专注于胃中存在的内源生长因子如何控制壁细胞的分化模式。子项目4检查胃上皮通过肠化生(胃细胞特性的改变)对胃中的炎症和/或细菌过度生长作出反应的途径；将检查在子项目3中确定的途径的作用。两个核心将协助PPG调查人员执行细胞生物学技术(核心A)和管理计划(核心B)。这两个核心将加强这四名调查员在各部门之间已经很强的互动。总体而言，这个PPG应用程序将加深我们对细胞如何做出鉴定和分化决策的理解 在胃肠道的胃和肠，并将提供线索，这种身份可能在病理状态下改变。

DESCRIPTION (provided by applicant): The Program Project Grant (PPG), " Cellular Decisions of Differentiation in the GI Tract" integrates the efforts of four investigators (two basic science and two clinical) from three Departments of the University of Michigan Medical School. The central goals of the work proposed in the PPG are: (a) To understand how epithelial cells in the upper gastrointestinal tract acquire their identity, both with respect to tissue identity (gastric vs. small intestine) and lineage identity (enteroendocrine cell vs. enterocyte or goblet cell) during ontogeny; (b) To investigate how the patterns of cellular differentiation in the acidsecreting epithelium of the stomach are normally controlled through specific intracellular pathways and how these pathways are altered by pathological insults (such insults can cause an alteration in identity of the gastric epithelium, such that it acquires a small intestinal phenoytpe). Subproject #1 examines the cis and trans factors that control identity in the intestinal epithelial cell, from a tissue-specific standpoint (stomach versus intestine), a regional standpoint (duodenum vs. distal intestine) and a differentiation standpoint (crypt vs. tip). In addition, in conjunction with Subprojects #2 and #4, the question of how gene regulation changes when stomach cells acquire intestinal identity (intestinal metaplasia) after pathological insult will be examined. Subproject #2 will trace the development of the enteroendocrine cell lineage within the intestine using cholecystokinin (CCK) as an early marker for this cell compartment. This work will utilize regulatory transgenes generated in Subproject #1. Subproject #3 will focus on how endogenous growth factors present in the stomach control the pattern of differentiation of the parietal cell. Subproject #4 examines the pathways through which the gastric epithelium responds to inflammation and/or bacterial overgrowth in the stomach through the generation of intestinal metaplasia, an alteration in gastric cell identity; the role of the pathways identified in Subproject #3 will be examined. Two Cores will assist the PPG investigators in the performance of Cell Biology techniques (Core A) and with Administration of the program (Core B). Both Cores will enhance the already strong interaction between these four investigators across Departmental lines. Overall, this PPG application will further our understanding of how cells make decisions of identity and differentiation in the stomach and intestine of the GI tract and will provide clues as to how this identity may be altered in pathological states.