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: 7582275
• 负责人: DEBORAH C. RUBIN
• 金额: $ 30.54万
• 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 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7582275
• 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（由申请人提供）：上皮间质相互作用是肠道形态发生过程中所必需的，并且在上皮癌发生中发挥关键作用 Epimorphin 是一种与分泌囊泡对接蛋白突触蛋白家族同源的间充质/肌成纤维细胞蛋白。 /- (Epi-/-) 小鼠，可存活，但小肠长度、粘膜表面积增加， Epi-/-小鼠的隐窝细胞增殖和隐窝裂变受到葡聚糖硫酸钠诱导的部分保护，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的影响。 -¿ - 连环蛋白和 Hedgehog (Hh) 信号通路 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生率显着增加，并且偶尔会发展为侵袭性癌症。 假设是 1. Epimorphin 是一种基质抑制剂。肠道上皮增殖的影响，其通过直接调节 Bmp 和其他肌成纤维细胞生长因子的合成和/或分泌发挥作用。 2. Epimorphin 通过调节来防止息肉形成。 3. Epimorphin缺失通过减少基质Bmp和其他生长因子的分泌从而调节wnt-¿而导致肠息肉病和癌变。 -连环蛋白和 Hh 信号通路。 4. Epimorphin 缺失可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. Epimorphin 的长期缺失将增强损伤/慢性炎症癌症模型中的肿瘤形成。确定 Epimorphin 缺失如何导致隐窝细胞增殖和小肠息肉形成增强 2. 使用 阐明肌成纤维细胞 Epimorphin 抑制上皮增殖的机制。 3. 确定表吗啡缺失改善 DSS 诱导的损伤的机制，以及这是否会增强与 DSS 诱导的损伤/炎症相关的癌发生 意义：我们有一个独特的小肠息肉形成和癌发生模型。 Epi-/-小鼠模型提出了一种调节隐窝细胞增殖的新范例，即隐窝细胞增殖。裂变和小肠息肉形成，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、癌发生以及上皮损伤和修复过程中的作用的工具。