Epithelial-Mesenchymal Interactions in Gut Morphogenesis

描述（由申请方提供）：上皮-间充质相互作用是个体发育期间肠道形态发生所必需的，并在上皮癌发生中起关键作用。表吗啡肽是一种间充质/肌成纤维细胞蛋白，与分泌囊泡停靠蛋白的突触融合蛋白家族具有同源性。我们产生了表吗啡-/-（Epi-/-）小鼠，其是可存活的，但具有增加的小肠长度、粘膜表面积、隐窝细胞增殖和隐窝分裂。Epi-/-小鼠部分地免受葡聚糖硫酸钠诱导的急性结肠炎的影响。我们的数据表明，Epi-/-小鼠的肠道表型来源于对骨形态发生蛋白（Bmp）、wnt-<$-连环蛋白和Hedgehog（Hh）信号通路的影响。这与我们的观察结果一致，即老年Epi-/-小鼠小肠腺瘤性息肉的发病率显著增加，偶尔会发生浸润性癌症。假设是1。表吗啡肽是肠道中上皮增殖的基质抑制剂，其通过直接调节Bmps和其他肌成纤维细胞生长因子的合成和/或分泌起作用。2.表吗啡通过调节隐窝细胞增殖和分裂来防止息肉形成。3.表吗啡肽缺失通过减少基质Bmp和其他生长因子的分泌，从而调节wnt-<$-连环蛋白和Hh信号通路，使肠息肉病和癌变易感。4.表吗啡肽缺失通过增加急性损伤后隐窝细胞增殖促进结肠上皮修复。5.在损伤/慢性炎症癌症模型中，表吗啡肽的长期损失将增强肿瘤形成。具体目标是：1。确定表吗啡肽缺失如何导致隐窝细胞增殖和小肠息肉形成增强。2.阐明肌成纤维细胞表吗啡肽抑制上皮细胞增殖的机制，使用肌成纤维细胞-上皮细胞共培养。3.确定表吗啡肽缺失改善DSS诱导的损伤的机制，以及这是否增强了与DSS诱导的损伤/炎症相关的致癌作用。意义：我们有一个独特的小肠息肉形成和癌变的模型，由单个肌成纤维细胞基因缺失产生。Epi-/-小鼠模型为调节隐窝细胞增殖、隐窝分裂和小肠息肉形成提供了一种新的范例，并为我们提供了定义肌成纤维细胞及其分泌产物在肠上皮稳态、癌变和上皮损伤和修复过程中的作用的工具。

DESCRIPTION (provided by applicant): Epithelial-mesenchymal interactions are required during ontogeny for gut morphogenesis and serve a critical role in epithelial carcinogenesis. Epimorphin is a mesenchymal/myofibroblast protein with homology to the syntaxin family of secretory vesicle docking proteins. We generated Epimorphin-/- (Epi-/-) mice, which are viable yet have increased small bowel length, mucosal surface area, crypt cell proliferation and crypt fission. Epi-/- mice were partially protected from acute colitis induced by dextran sodium sulfate. Our data suggest that the gut phenotype of the Epi-/- mouse derives from effects on bone morphogenetic protein (Bmp), wnt-¿- catenin and Hedgehog (Hh) signaling pathways. This is consistent with our observation that aged Epi-/- mice have a significantly increased incidence of small bowel adenomatous polyps, and occasionally develop invasive cancer. The hypotheses are 1. Epimorphin is a stromal inhibitor of epithelial proliferation in the gut, which acts by directly regulating synthesis and/or secretion of Bmps and other myofibroblast growth factors. 2. Epimorphin protects against polyp formation by modulating crypt cell proliferation and fission. 3. Epimorphin deletion predisposes to intestinal polyposis and carcinogenesis by reducing secretion of stromal Bmp and other growth factors, thus modulating wnt-¿-catenin and Hh signaling pathways. 4. Epimorphin deletion enhances colonic epithelial repair by increasing crypt cell proliferation after acute injury. 5. Long term loss of epimorphin will enhance tumor formation in an injury/chronic inflammation cancer model. The Specific Aims are: 1. Determine how epimorphin deletion leads to enhanced crypt cell proliferation and small intestinal polyp formation. 2. Clarify mechanisms by which myofibroblast epimorphin inhibits epithelial proliferation, using myofibroblast-epithelial co-cultures. 3. Determine mechanisms by which epimorphin deletion ameliorates injury induced by DSS, and whether this enhances carcinogenesis associated with DSS-induced injury/inflammation. Significance: we have a unique model of small bowel polyp formation and carcinogenesis, produced by deletion of a single myofibroblast gene. The Epi-/- mouse model has suggested a novel paradigm for the regulation of crypt cell proliferation, crypt fission, and small bowel polyp formation and has provided us with the tools to define the role of myofibroblasts and their secretory products in gut epithelial homeostasis, carcinogenesis and in epithelial injury and repair processes.