The role of SPRY2 in the colonic epithelial response to inflammation

项目摘要/摘要 这些研究旨在测试一种新的想法，即Sprouty-2(SPRY2)，一种受体的细胞内调节因子 酪氨酸激酶诱导的信号转导，是限制结肠上皮修复反应的中央守门人 包括在分泌分化和伤口愈合方面的保护性变化。我们的初步数据显示， 结肠上皮中的炎症下调了SPRY2的表达。这似乎是一种保护性的或 代偿反应，因为肠道上皮特异性SPRY2缺失的小鼠对葡聚糖具有抵抗力 硫酸钠(DSS)诱导的结肠炎。此外，这些小鼠表现出细胞内信号的改变，升高 白介素IL-33水平升高，绒毛细胞增多，粘液产生增加。因此，受监管的SPRY2损失可能 是帮助修复结肠上皮屏障的一个重要的、潜在可利用的机制 在一次侮辱之后。在这个项目中，我们将测试结肠炎导致SPRY2释放丢失的假设 正常的动态平衡抑制细胞内信号以促进保护性上皮和上皮- 间充质反应。本研究的目的是：(1)明确SPRY2对结肠分泌细胞的影响 分化和功能；(2)检测SPRY2在上皮创伤修复中的作用；以及(3)确定 SPRY2的下调促进了结肠炎的恢复。我们将在体外用协调的方法检验中心假说 体内模型包括人和小鼠的原代结肠上皮培养，细胞培养模型，以及 活体结肠炎使用条件性基因敲除小鼠或其中SPRY2水平通过 纳米颗粒传递的表达构建物。

PROJECT SUMMARY/ABSTRACT These studies are designed to test the novel idea that Sprouty-2 (SPRY2), an intracellular regulator of receptor tyrosine kinase-induced signaling, is a central gatekeeper restricting colonic epithelial repair responses including protective changes in secretory differentiation and wound healing. Our preliminary data show that SPRY2 is downregulated by inflammation in the colonic epithelium. This appears to be a protective or compensatory response, as mice with intestinal epithelium-specific SPRY2 deletion are resistant to dextran sulfate sodium (DSS)-induced colitis. Furthermore, these mice display altered intracellular signaling, elevated interleukin IL-33 levels, more tuft cells, and increased mucus production. Thus, a regulated loss of SPRY2 may be an important, potentially exploitable, mechanism contributing to repair of the colonic epithelial barrier following an insult. In this project, we will test the hypothesis that colitis-induced loss of SPRY2 releases normal homeostatic inhibition of intracellular signaling to promote protective epithelial and epithelial- mesenchymal responses. Aims of the study are (1) define the influence of SPRY2 on colonic secretory cell differentiation and function; (2) test the role of SPRY2 in epithelial wound repair, and (3) determine whether SPRY2 downregulation drives recovery from colitis. We will test the central hypothesis with coordinated in vitro and in vivo models including human and mouse primary colonic epithelial culture, cell culture models, and in vivo colitis using conditional knockout mice or mice in which SPRY2 levels are manipulated through nanoparticle-delivered expression constructs.