Growth Factor Signaling in Intestinal Development

肠道发育中的生长因子信号传导

• 批准号: 7059143
• 负责人: STEVEN M COHN
• 金额: $ 2.24万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7059143
• 关键词: Growth; Factor; Signaling; Intestinal; Development

DESCRIPTION (provided by applicant): Epithelia, such as those lining the gastrointestinal tract, are able to undergo continuous self-renewal; they contain a population of undifferentiated stem cells that have a large capacity for self renewal and can also give rise to daughter cells which are able to differentiate into all of the mature cell types needed for normal function of the epithelial layer. The nature of the signals that mediate the establishment of this hierarchical organization of the epithelium during normal gastrointestinal development has not yet been defined. Fibroblast growth factors (FGFs) are a family of at least 23 related mesenchymaly-derived peptide growth factors that modulate a wide array of morphogenic and differentiation events occurring during normal ontogeny of a variety of tissues. We have recently found that the expression of one FGF receptor gene, FGFR-3, is restricted to undifferentiated cells in the lower two-thirds of the intestinal crypt epithelium and is maximally expressed during crypt morphogenesis. Additionally, preliminary studies of intestinal development in FGFR3-/- mice, demonstrate that FGFR-3 regulates both the rate of nascent crypt formation and the number of replicating crypt transit cells in the suckling mouse intestine. The central hypothesis of this proposal is that signaling through FGFR-3 regulates the fate and/or proliferation of the multipotent epithelial stem cells during normal intestinal ontogeny. Aim 1 is to determine whether FGFR-3-mediated signaling directly regulates expansion of the epithelial stem cell population during normal intestinal development through effects on stem cell proliferation and/or programmed cell death. Mice with targeted mutations in the FGFR3 receptor gene will be used to determine the effects of FGFR3 mediated signaling on the number of clonogenic stem cells and on apoptosis at various developmental time points. Aim 2 will examine whether the effects of FGFR3 on crypt morphogenesis are mediated through a 13-catenin/TCF-4 dependent mechanism. Evidence in the literature suggests that the HMG transcription factors TCF-4 and Lef-1 are important downstream regulatory mediators of proliferative and apoptotic events in the crypt epithelium. Both cell culture and animal models will be used to determine whether signaling through FGFR3 can modulate TCF-4 activity. The goal of aim 3 is to define the intermediate signaling cascades that FGFR3 uses to regulate morphogenic events during intestinal development. The operant FGFR3 signaling pathways in intestinal epithelial cell lines, especially those impinging on TCF-4, will be investigated using a combination of biochemical and molecular approaches.

描述（由申请人提供）：上皮细胞，例如胃肠道内壁的上皮细胞，能够进行持续的自我更新；它们含有一群未分化的干细胞，具有很强的自我更新能力，并且还可以产生子细胞，这些子细胞能够分化成上皮层正常功能所需的所有成熟细胞类型。 在正常胃肠道发育过程中介导上皮细胞分层组织建立的信号的性质尚未明确。 成纤维细胞生长因子 (FGF) 是至少 23 种相关间充质衍生肽生长因子的家族，可调节多种组织正常个体发育过程中发生的多种形态发生和分化事件。 我们最近发现一种 FGF 受体基因 FGFR-3 的表达仅限于肠隐窝上皮下三分之二的未分化细胞，并且在隐窝形态发生期间表达最大。 此外，对 FGFR3-/- 小鼠肠道发育的初步研究表明，FGFR-3 调节乳鼠肠道中新生隐窝形成的速率和复制隐窝转运细胞的数量。 该提议的中心假设是，通过 FGFR-3 的信号传导在正常肠道个体发育过程中调节多能上皮干细胞的命运和/或增殖。 目标 1 是确定 FGFR-3 介导的信号传导是否通过影响干细胞增殖和/或程序性细胞死亡来直接调节正常肠道发育过程中上皮干细胞群的扩张。 FGFR3 受体基因靶向突变的小鼠将用于确定 FGFR3 介导的信号传导对克隆干细胞数量和不同发育时间点细胞凋亡的影响。 目标 2 将检查 FGFR3 对隐窝形态发生的影响是否通过 13-catenin/TCF-4 依赖性机制介导。 文献证据表明，HMG 转录因子 TCF-4 和 Lef-1 是隐窝上皮增殖和凋亡事件的重要下游调节介质。 细胞培养和动物模型将用于确定 FGFR3 信号传导是否可以调节 TCF-4 活性。 目标 3 的目标是定义 FGFR3 用于调节肠道发育过程中形态发生事件的中间信号级联。 将结合生化和分子方法来研究肠上皮细胞系中的 FGFR3 信号传导途径，特别是影响 TCF-4 的细胞系。