Epithelial-mesenchymal interactions in gut morphogenesis

肠道形态发生中的上皮-间质相互作用

• 批准号: 6743080
• 负责人: DEBORAH C. RUBIN
• 金额: $ 9.71万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6743080
• 关键词: biological signal transduction; bone morphogenetic proteins; cell cell interaction; cell differentiation; cell population study; embryo /fetus cell /tissue; embryo /fetus protein; gastrointestinal epithelium; gene expression; gene targeting; genetically modified animals; glycoproteins; growth /development; histogenesis; immunocytochemistry; in situ hybridization; intestines; laboratory mouse; laboratory rat; mammalian embryology; membrane proteins; mesenchyme; protein localization; protein structure function; tissue /cell culture; transcription factor

DESCRIPTION (Provided by Applicant): Epithelial-mesenchymal interactions are critical for the normal morphogenesis and maintenance of the crypt-villus axis. The molecules that regulate these reciprocal interactions have only recently begun to be described. We have identified a mesenchymal protein, epimorphin, as a putative regulator of epithelial morphogenesis. We show that this molecule has profound effects on morphogenesis and differentiation of the intestinal epithelium. However, the mechanism by which epimorphin exerts its effects is unknown, and the in vivo effects of inhibiting epimorphin expression in whole animals have not yet been described. Our hypothesis for this application is that epimorphin's effects are mediated, at least in part, by regulating the secretion o soluble substances that are important in morphogenesis. Based on our preliminary data, one such candidate may be sonic hedgehog (Shh)a critical regulator of gut-endodermal-mesenchymal signaling in early gut ontogeny. We show that blocking hedgehog signaling pathways by antibody infusion produces profound changes in postnatal gut morphology, with disorganized villi, runting and early death. These effects are recapitulated in vitro in an epithelial-myofibroblast co-culture model developed in our lab. The major hypotheses of the current proposal are: 1. Intestinal myofibroblasts produce epimorphin which regulates the formation and maintenance of the crypt-villus axis. 2. Hedgehog signaling pathways are required for the maintenance of the postnatal crypt-villus axis. The Specific Aims are: 1. Determine the mechanisms by which epimorphin induces crypt-villus morphogenesis and cytodifferentiation. 2. Determine the in vivo function of epimorphin by creating epimorphin -/- mice. 3. Determine whether the effects of hedgehog on postnatal epithelial morphogenesis and differentiation are mediated via epithelial-mesenchymal interactions, using an epithelial-myofibroblast co-culture system. The significance of this application is based on our recent identification of a mesenchymal/myofibroblast gene that plays an important role in the regulation of crypt-villus axis morphogenesis. A role for hedgehog signaling in postnatal gut ontogeny has also been established and will be further examined. Specific to the research scope for this RFA, these studies will characterize epithelial-mesenchymal cross talk underlying normal development. We will also establish a novel model, the epimorphin null mouse, for characterizing the molecular properties of the mesenchymal cell populations that regulate epithelial cell renewal in the developing and adult GI tract.

描述（由申请人提供）：上皮 - 间质相互作用对于正常形态发生至关重要 并维护隐窝villus轴。调节这些的分子 互相互作用直到最近才开始描述。我们有 鉴定出一种间充质蛋白，表达蛋白，作为推定的调节剂 上皮形态发生。我们表明该分子对 肠上皮的形态发生和分化。但是， 表达式发挥作用的机制尚不清楚，并且体内 抑制全动物中抑制表达表达的影响尚未 描述。我们对此应用的假设是表达的影响是 至少部分通过调节分泌o溶解性物质进行介导 在形态发生中很重要。基于我们的初步数据，一个这样的 候选人可能是声音刺猬（SHH） 早期肠道发育中的肠道内胚层 - 间质信号传导。我们表明 通过抗体输注阻断刺猬信号通路会产生深刻的 产后肠道形态的变化，绒毛杂乱无章的绒毛和早期 死亡。这些作用在上皮肌纤维细胞中在体外概括 在我们的实验室中开发的共培养模型。电流的主要假设 建议是：1。肠肌纤维细胞产生调节的表达 隐窝村轴的形成和维护。 2。刺猬信号 维持产后隐脚村轴需要途径。 具体目的是：1。确定表达诱导的机制 地crypt-villus形态发生和细胞分化。 2。确定体内 通过产生表达 - / - 小鼠的表达式吗啡的功能。 3。确定是否 刺猬对产后上皮形态发生和 通过上皮 - 间质相互作用介导分化，使用 上皮肌纤维细胞共培养系统。这一点的意义 应用是基于我们最近确定的 在调节中起重要作用的间充质/肌纤维细胞基因 隐窝磁轴形态发生。刺猬信号在产后的作用 还建立了肠病，将进一步检查。具体的 对于此RFA的研究范围，这些研究将表征 上皮 - 间质交叉谈话是正常发育的基础。我们也会 建立一个新型模型，表达式null小鼠，用于表征 调节的间充质细胞群的分子特性 发育中和成人胃肠道的上皮细胞更新。