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: 6788699
• 负责人: DEBORAH C. RUBIN
• 金额: $ 30.08万
• 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 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6788699
• 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 和隐窝绒毛轴的维护。调节这些的分子 直到最近才开始描述相互的相互作用。我们有 鉴定出一种间质蛋白，epimorphin，作为假定的调节剂 上皮形态发生。我们证明该分子对 肠上皮的形态发生和分化。然而， Epimorphin 发挥作用的机制尚不清楚，并且体内 抑制 Epimorphin 表达对整个动物的影响尚未得到证实 描述的。我们对此应用的假设是，epimorphin 的作用是 至少部分地通过调节可溶性物质的分泌来介导 这对于形态发生很重要。根据我们的初步数据，其中一项 候选人可能是音速刺猬（Shh），一个关键的调节者 早期肠道个体发育中的肠道-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产生深远的影响 产后肠道形态的变化，绒毛紊乱、矮小和早产 死亡。这些效应在体外的上皮肌成纤维细胞中得到重现 我们实验室开发的共培养模型。目前的主要假设 建议是： 1. 肠肌成纤维细胞产生 Epimorphin，调节 隐窝-绒毛轴的形成和维持。 2. Hedgehog信号 维持出生后隐窝-绒毛轴需要通路。 具体目标是： 1. 确定 Epimorphin 诱导的机制 隐窝绒毛形态发生和细胞分化。 2.体内测定 通过创建 Epimorphin -/- 小鼠来发挥 Epimorphin 的功能。 3. 判断是否 刺猬对出生后上皮形态发生的影响 分化是通过上皮-间质相互作用介导的，使用 上皮-肌成纤维细胞共培养系统。此举的意义 应用程序是基于我们最近识别的 在调节中起重要作用的间充质/肌成纤维细胞基因 隐窝-绒毛轴形态发生的影响。刺猬信号在产后的作用 肠道个体发育也已建立并将进一步检查。具体的 就本次 RFA 的研究范围而言，这些研究将描述 上皮-间质串扰是正常发育的基础。我们也会 建立一种新的模型，即表吗啡无效小鼠，用于表征 调节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。