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: 7787117
• 负责人: DEBORAH C. RUBIN
• 金额: $ 30.23万
• 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 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7787117
• 关键词: Acute; Address; Adenomatous Polyps; Area; Biological Models; Biological Process; Bone Morphogenetic Proteins; Cancer Model; Carcinoma; Cell Proliferation; Characteristics; Chronic; Coculture Techniques; Colitis; Colon; Data; Docking; Epithelial; Erinaceidae; Family; Genes; Growth; Growth Factor; Histologic; Homeostasis; Incidence; Inflammation; Injury; Intestinal Polyposis; Intestinal Polyps; Intestines; Length; Malignant - descriptor; Malignant Neoplasms; Manuscripts; Mediating; Mesenchymal; Modeling; Morphogenesis; Mus; Myofibroblast; Nuclear; Pathway interactions; Phenotype; Polyps; Process; Proteins; Regulation; Role; Secretory Vesicles; Severities; Signal Pathway; Signal Transduction; Small Intestinal Polyp; Small Intestines; Sodium Dextran Sulfate; Surface; Time; Vesicle; aged; carcinogenesis; colon carcinogenesis; colonic crypt; crypt cell; epimorphin; in vitro Model; inhibitor/antagonist; injury and repair; member; mouse model; novel; overexpression; polyposis; protective effect; repaired; smoothened signaling pathway; syntaxin; tool; tumor; tumorigenic

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.

描述（由适用提供）：肠道形态发生期间需要上皮 - 间充质相互作用，并在上皮癌发生中起关键作用。上皮是一种间充质/成肌纤维细胞蛋白，与索引素的秘密蔬菜家族有同源性。我们产生了上皮 - / - （EPI - / - ）小鼠，它们可行，但肠长度较小，粘膜表面积，加密细胞增殖和加密裂变。 EPI - / - 小鼠被部分保护免受硫酸葡萄糖钠诱导的急性结肠炎。我们的数据表明，EPI - / - 小鼠的肠道表型源自对骨形态发生蛋白（BMP），Wnt-®-catenin和刺猬（HH）信号通路的影响。这与我们的观察结果一致，即老化的Epi - / - 小鼠的小肠腺瘤息肉的发病率显着增加，偶尔会产生侵入性癌症。假设是1。表达蛋白是肠道中上皮增殖的基质抑制剂，该抑制剂是通过直接恢复BMPS和其他肌纤维细胞生长因子的合成和/或分泌而起作用的。 2。表达蛋白通过调节隐窝细胞增殖和裂变来预防息肉形成。 3。通过减少基质BMP和其他生长因子的分泌，表达式缺失易于肠道息肉和致癌作用，从而调节Wnt -¿ -catenin和HH信号传导途径。 4。表达式缺失通过增加急性损伤后的隐窝细胞增殖来增强结肠上皮修复。 5。表达的长期丧失将增强损伤/慢性炎症癌症模型中的肿瘤形成。具体目的是：1。确定表达式缺失如何导致加密细胞增殖增强和小肠息肉的形成。 2。阐明肌成纤维细胞表达的机制，使用肌纤维细胞上皮共培养抑制上皮增殖。 3。确定表达式缺失可以改善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模型，该模型是通过单个肌纤维细胞基因的缺失产生的。 Epi - / - 小鼠模型已被提出一种新型的范式，用于调节隐窝细胞增殖，隐窝裂变和小肠息肉形成，并为我们提供了定义肌纤维细胞及其分泌产物在肠道上皮稳态，癌和上皮损伤和上皮造成的工具中的作用的工具。