Cellular Decisions of Differentiation in the GI Tract

描述（由申请人提供）： 该计划项目补助金（PPG），“在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中提出的工作的中心目标是：（a）了解上消化道上皮细胞如何获得其身份，包括组织身份（胃与小肠）和谱系身份（肠内分泌细胞与肠上皮细胞或杯状细胞）;（B）研究胃泌酸上皮细胞分化的模式如何通过特定的细胞内途径正常控制，以及这些途径如何被病理性损伤改变（这种损伤可引起胃上皮细胞特性的改变，使得其获得小肠表型）。子项目#1从组织特异性的角度（胃与肠），区域的角度（十二指肠与远端肠）和分化的角度（隐窝与尖端）检查控制肠上皮细胞身份的顺式和反式因子。此外，结合子项目#2和#4，将研究当胃细胞在病理损伤后获得肠特性（肠化生）时基因调控如何变化的问题。子项目#2将使用胆囊收缩素（CCK）作为该细胞室的早期标记物来追踪肠内分泌细胞谱系的发展。这项工作将利用子项目#1中产生的调控转基因。子项目#3将集中在如何内源性生长因子存在于胃控制壁细胞的分化模式。子项目#4检查胃上皮通过肠上皮化生（胃细胞身份的改变）对胃中炎症和/或细菌过度生长做出反应的途径;将检查子项目#3中确定的途径的作用。两个核心将协助PPG研究者进行细胞生物学技术（核心A）和项目管理（核心B）。这两个核心将加强这四名调查员之间跨部门的强有力的互动。总的来说，PPG的应用将进一步加深我们对细胞如何决定身份和分化的理解。 在胃肠道的胃和肠中，并将提供关于这种身份如何在病理状态下改变的线索。

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.