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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要这些研究旨在测试 Sprouty-2 (SPRY2) 受体的细胞内调节剂这一新想法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央看门人包括分泌分化和伤口愈合的保护性变化。我们的初步数据表明 SPRY2 因结肠上皮炎症而下调。这似乎是一种保护或补偿反应，因为肠上皮特异性 SPRY2 缺失的小鼠对葡聚糖具有抵抗力硫酸钠（DSS）诱发的结肠炎。此外，这些小鼠表现出细胞内信号传导的改变，白细胞介素 IL-33 水平、更多簇细胞和粘液产生增加。因此，SPRY2 的调节性丢失可能是有助于修复结肠上皮屏障的重要的、潜在可利用的机制受到侮辱后。在这个项目中，我们将测试结肠炎引起的 SPRY2 释放缺失的假设细胞内信号传导的正常稳态抑制，促进保护性上皮和上皮- 间质反应。研究目的是（1）明确SPRY2对结肠分泌细胞的影响分化和功能； (2)测试SPRY2在上皮伤口修复中的作用，以及(3)确定是否 SPRY2 下调可促进结肠炎的恢复。我们将通过体外协调测试中心假设和体内模型，包括人和小鼠原代结肠上皮培养、细胞培养模型和使用条件敲除小鼠或通过以下方式操纵 SPRY2 水平的小鼠体内结肠炎纳米颗粒递送的表达构建体。