Regulation of Colon Epithelial Cell Survival by NRG4-ErbB4 Signaling

NRG4-ErbB4 信号传导对结肠上皮细胞存活的调节

基本信息

批准号：
9063537
负责人：
Mark R Frey
金额：
$ 35.24万
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：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9063537
关键词：
Acute Affect Apoptosis Apoptotic Biology Cell Culture Techniques Cell Survival Chronic Colitis Colon Data Development Down-Regulation Effectiveness Epidermal Growth Factor Receptor Epithelial Epithelial Cells Epithelium ErbB4 gene Family Future Gastrointestinal Diseases Gene Expression Growth Factor Receptors Health Human In Vitro Inflammation Inflammation Mediators Inflammatory Inflammatory Bowel Diseases Injury Interleukin-10 Intestines Knock-out Ligand Binding Ligands Mediating Modeling Molecular Mus Myofibroblast Pathology Pathway interactions Peptides Predisposition Property Protein Tyrosine Kinase Receptor Protein-Tyrosine Kinases Regulation Research Design Role STAT1 gene Severities Signal Pathway Signal Transduction Signaling Molecule TNF gene Testing Therapeutic Up-Regulation cellular targeting colonic crypt cytokine design improved improved outcome in vivo in vivo Model innovation loss of function migration neuregulin-4 novel novel therapeutics overexpression protective effect repaired research study response therapeutic target

项目摘要

DESCRIPTION (provided by applicant): The ErbB4 receptor tyrosine kinase is induced by inflammation in the colon epithelium, and ErbB4 overexpression promotes colonocyte survival in vitro without affecting proliferation or migration. Thus, ErbB4 induction may be a compensatory response meant to protect the epithelium. However, preliminary data developed for this application show that expression of the specific ErbB4 ligand neuregulin-4 (NRG4) is deficient in both human IBD and murine colitis. Furthermore, in murine colitis models, although ErbB4 expression is elevated, it is not phosphorylated/activated. These results suggest that, in the context of inflammation, NRG4 downregulation leads to deficient signaling despite ErbB4 upregulation. Additional preliminary studies show that exogenous NRG4 protects colonocytes from cytokine-induced apoptosis both in vitro and in vivo, and reduces the severity of acute murine DSS colitis. We propose therefore that NRG4 could be used to stimulate ErbB4 during colitis, and thus to inhibit colonocyte apoptosis and improve pathology. As ErbB4 (a) has ligand binding properties and downstream targets that are unique among tyrosine kinases, and (b) can directly associate with both anti-apoptotic signaling molecules (e.g., PI3K, Src) and inflammatory mediators (e.g., STAT1), it has significant potential as a novel and selective IBD therapeutic target. However, neither the role of ErbB4 in colon biology in vivo nor the colonic response to its selective activation has been defined. Therefore, this project is designed to test the hypothesis that downregulation of NRG4 worsens colitis, and thus exogenous NRG4 treatment may improve colitis by activating anti-apoptotic signaling in colon epithelial cells. Planned experiments will use coordinated cell culture, crypt culture, and in vivo models to (1) determine the effects of loss of NRG4-ErbB4 function on colitis and define the mechanisms of NRG4 loss, (2) test the effectiveness of exogenous NRG4 in colitis, and (3) define signaling pathways which are required for NRG4-induced colon epithelial cell survival. Together, these studies will investigate the exciting possibility that NRG4-ErbB4 signaling is a novel therapeutic avenue for IBD.

描述（申请人提供）：ErbB4受体酪氨酸激酶由结肠上皮炎症诱导，ErbB4过表达促进结肠细胞体外存活而不影响增殖或迁移。因此，ErbB4 诱导可能是一种旨在保护上皮的补偿反应。然而，为此应用开发的初步数据表明，在人类 IBD 和小鼠结肠炎中，特异性 ErbB4 配体神经调节蛋白-4 (NRG4) 的表达均存在缺陷。此外，在小鼠结肠炎模型中，尽管 ErbB4 表达升高，但它并未被磷酸化/激活。这些结果表明，在炎症情况下，尽管 ErbB4 上调，但 NRG4 下调会导致信号传导缺陷。其他初步研究表明，外源性 NRG4 可在体外和体内保护结肠细胞免受细胞因子诱导的细胞凋亡，并降低急性小鼠 DSS 结肠炎的严重程度。因此，我们建议NRG4可用于在结肠炎期间刺激ErbB4，从而抑制结肠细胞凋亡并改善病理学。由于 ErbB4 (a) 具有酪氨酸激酶中独特的配体结合特性和下游靶标，并且 (b) 可以直接与抗凋亡信号分子（例如 PI3K、Src）和炎症介质（例如 STAT1）相关，因此具有作为新型选择性 IBD 治疗靶点的巨大潜力。然而，ErbB4 在体内结肠生物学中的作用以及结肠对其选择性激活的反应都尚未确定。因此，该项目旨在检验NRG4下调会加重结肠炎的假设，因此外源性NRG4治疗可能通过激活结肠上皮细胞中的抗凋亡信号传导来改善结肠炎。计划的实验将使用协调的细胞培养、隐窝培养和体内模型来（1）确定NRG4-ErbB4功能丧失对结肠炎的影响并确定NRG4丧失的机制，（2）测试外源NRG4在结肠炎中的有效性，(3) 定义 NRG4 诱导的结肠上皮细胞存活所需的信号传导途径。这些研究将共同探讨 NRG4-ErbB4 信号传导是 IBD 的一种新治疗途径的令人兴奋的可能性。