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：
8629735
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/8629735
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 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 Treatment outcome Up-Regulation cellular targeting colonic crypt cytokine design improved in vivo in vivo Model innovation loss of function migration neuregulin-4 novel novel therapeutics overexpression protective effect public health relevance 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（由申请人提供）：ERBB4受体酪氨酸激酶是由结肠上皮的炎症诱导的，而ERBB4过表达在体外促进了结肠细胞的存活，而不会影响增殖或迁移。因此，ERBB4诱导可能是旨在保护上皮的补偿性反应。然而，本申请为此开发的初步数据表明，特定的ERBB4配体神经蛋白-4（NRG4）的表达在人IBD和鼠结肠炎中均缺乏。此外，在鼠结肠炎模型中，尽管ERBB4表达升高，但并未被磷酸化/激活。这些结果表明，在炎症的背景下，尽管ERBB4上调，NRG4下调导致信号不足。其他初步研究表明，外源性NRG4可保护结肠细胞在体外和体内免受细胞因子诱导的凋亡，并降低急性鼠DSS结肠炎的严重程度。因此，我们建议NRG4可用于刺激结肠炎期间的ERBB4，从而抑制结肠细胞凋亡并改善病理。由于ERBB4（a）具有在酪氨酸激酶中独有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）和炎症介导器和炎症介导器（例如STAT1）直接相关联（例如PI3K，SRC），因此它具有重要的潜力。但是，ERBB4在体内结肠生物学中的作用均未定义，以及对其选择性激活的结肠反应。因此，该项目旨在检验以下假设：NRG4的下调会使结肠炎恶化，因此外源性NRG4治疗可以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。 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.总之，这些研究将研究NRG4-ERBB4信号传导是IBD的一种新型治疗途径的令人兴奋的可能性。