The role of SPRY2 in the colonic epithelial response to inflammation

SPRY2在结肠上皮炎症反应中的作用

• 批准号: 10409691
• 负责人: Mark R Frey
• 金额: $ 38.05万
• 依托单位: CHILDREN'S HOSPITAL OF LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-20 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10409691
• 关键词: 1-Phosphatidylinositol 3-Kinase; Acute; Affect; Agonist; Biological Assay; Biology; Cell Count; Cell Culture Techniques; Cell Differentiation process; Cell model; Cell physiology; Cells; Chronic; Colitis; Colon; Cultured Cells; Cytokine Signaling; Data; Development; Disease; Down-Regulation; Epithelial; Epithelial Cells; Equilibrium; Experimental Models; Exposure to; Future; Gatekeeping; Goblet Cells; Growth Factor; Homeostasis; Human; In Vitro; Inflammation; Inflammatory Bowel Diseases; Injury; Interleukin-10; Interleukin-13; Interleukins; Intestines; Knock-out; Knockout Mice; Maintenance; Mediator of activation protein; Mesenchymal; Mesenchyme; Mitogen-Activated Protein Kinases; Modeling; Molecular; Morphogenesis; Mucous body substance; Mus; Natural regeneration; Pathogenicity; Pathologic; Pathology; Pathway interactions; Permeability; Physiology; Play; Process; Production; Receptor Protein-Tyrosine Kinases; Recovery; Repression; Resistance; Role; Secretory Cell; Signal Transduction; System; Testing; Transgenic Organisms; WNT Signaling Pathway; cell motility; cellular targeting; conditional knockout; cytokine; design; dextran sulfate sodium induced colitis; epithelial repair; epithelial wound; in vivo; in vivo Model; inhibitor; intestinal epithelium; knock-down; nanoparticle delivery; novel; overexpression; repaired; response; villin; wound healing

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.

项目总结/摘要 这些研究旨在验证Sprouty-2（SPRY 2），一种受体的细胞内调节因子， 酪氨酸激酶诱导的信号传导是限制结肠上皮修复反应的中心守门人 包括分泌分化和伤口愈合的保护性变化。初步数据显示， SPRY 2通过结肠上皮中的炎症下调。这似乎是一种保护性或 代偿性反应，因为肠上皮特异性SPRY 2缺失的小鼠对葡聚糖耐药 硫酸钠（DSS）诱导结肠炎。此外，这些小鼠显示出改变的细胞内信号传导， 白细胞介素IL-33水平，更多的簇状细胞和增加的粘液产生。因此，SPRY 2的调节性丢失可能 是一个重要的，潜在的开发，机制有助于修复结肠上皮屏障 在侮辱之后。在这个项目中，我们将测试结肠炎引起的SPRY 2释放损失的假设， 正常的稳态抑制细胞内信号传导，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SPRY 2对结肠分泌细胞的影响 分化和功能;（2）测试SPRY 2在上皮创伤修复中的作用，以及（3）确定SPRY 2是否 SPRY 2下调驱动结肠炎的恢复。我们将测试中心假设与协调在体外 和体内模型，包括人和小鼠原代结肠上皮培养物、细胞培养模型，以及体内模型， 使用条件性敲除小鼠或SPRY 2水平通过以下操作的小鼠的体内结肠炎 纳米颗粒递送的表达构建体。