Regulation of GI & Neural Epithelial Cell Proliferation

地理标志的监管

• 批准号: 6922884
• 负责人: BIBHUTI B MISHRA
• 金额: $ 25.12万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6922884
• 关键词: actins; ankyrins; binding sites; biological signal transduction; brain; cell proliferation; chimeric proteins; confocal scanning microscopy; gastrointestinal epithelium; neurogenesis; phosphorylation; protein localization; protein protein interaction; spectrin; tissue /cell culture; transfection; transforming growth factors

DESCRIPTION: (Adapted from the Applicant's Abstract): SMAD proteins are intracellular signaling molecules of TGF-beta and have been shown to play a pivotal role in gastrointestinal carcinogenesis. The applicant's group has recently reported a novel phenotype with heterozygous Smad 2/3 knockout intercrosses, with all mutants dying at E14 with marked liver hypoplasia and holoprosencephaly. The Smad 2/3 mutants were notable for a marked fall in the expression of ELF 3, a beta-spectrin previously cloned by the applicant's group. Antisense studies suggest a crucial role for ELF 3 in biliary epithelial cell formation. In addition, Smad 2 and Smad 3 bind to ELF3. Experiments in this proposal are aimed at testing the hypothesis that ELF 3 plays a pivotal role in TGF-beta signaling involving both gastrointestinal and anterior cranial development. The specific aims are: 1. (i) To determine the phenotypic and molecular basis of the size heterogeneity of ELF proteins, and (ii) to test whether ELF can associate with other signal transducing proteins to gain an understanding of the mechanism of action of ELF. 2. (i) To characterize the interaction of ELF with Smads and to define the domains in Smads that bind ELF, (ii) to confirm interaction of ELF and Smads by co-immunoprecipitation experiments, and (iii) to investigate whether TGF-beta receptor-mediated phosphorylation of Smads or ELF may regulate their interaction. 3. To study the functional importance of ELF in TGF-beta signaling by defining the domains in ELF that interact with Smad 2, its subcellular localization, and its association with the TGF-beta receptor. 4. To determine whether ELF regulates the subcellular localization of Smad 2 and Smad 3 based on the preliminary evidence suggesting that ELF functions upstream of the Smad signaling pathway. These studies should lead to a greater understanding of the specific role Smad 2, Smad 3, and cytoskeletal proteins such as ELF in both gastrointestinal and anterior cranial development.

描述：（根据申请人的摘要改编）：Smad蛋白是 TGF-β的细胞内信号传导分子已显示出来 在胃肠道癌发生中关键作用。申请人的小组有 最近报道了一种具有杂合SMAD 2/3敲除的新表型 间交叉，所有突变体在E14死亡，具有明显的肝发育不全和 全脑脑。 SMAD 2/3突变体在明显的跌落中引人注目 ELF 3的表达，这是一种先前由申请人克隆的β-光谱蛋白 团体。反义研究表明ELF 3在胆道上皮中的至关重要作用 细胞形成。另外，SMAD 2和SMAD 3与ELF3结合。实验 该提案旨在测试Elf 3的假设 在涉及胃肠道和前颅内的TGF-β信号传导中的作用 发展。具体目的是：1。（i）确定表型和 ELF蛋白质大小异质性的分子基础，以及（II）测试 小精灵是否可以与其他信号转导蛋白相关联以获得 理解精灵作用机理。 2。（i）表征 小精灵与smads的相互作用，并定义结合小精灵的smads中的域 （ii）通过共免疫沉淀确认精灵和SMAD的相互作用 实验和（iii）研究TGF-β受体介导的是否介导 SMAD或ELF的磷酸化可能调节其相互作用。 3。研究 通过定义域中的tgf-beta信号传导中精灵的功能重要性 与Smad 2相互作用的精灵，其亚细胞定位及其 与TGF-β受体的关联。 4。确定精灵是否调节 基于初步的SMAD 2和SMAD 3的亚细胞定位 证据表明ELF功能在SMAD信号通路的上游。 这些研究应该使人们对特定作用SMAD有更深入的了解 2，Smad 3和细胞骨架蛋白，例如胃肠道和 前颅前发育。