The role of the ErbB4 and ErbB3 neuregulin receptors in intestinal epithelial regeneration

ErbB4 和 ErbB3 神经调节蛋白受体在肠上皮再生中的作用

基本信息

批准号：
10163158
负责人：
Mark R Frey
金额：
$ 42.17万
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 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10163158
关键词：
Acute Apoptosis CD3 Antigens Cell Count Cell Differentiation process Cells Censuses Chronic Data Development Enterocytes Epithelial Epithelial Cells Equilibrium ErbB4 gene Funding Future Gastrointestinal Injury Growth Factor Health Heterodimerization Homeostasis Hypoxia Inducible Factor Inflammatory Inflammatory Bowel Diseases Injury Intestines Knowledge LGR5 gene Ligands Link MAP Kinase Gene Modeling Molecular Mus NRG1 gene Natural regeneration Neuregulin Receptor Neuregulins Paneth Cells Pathway interactions Patients Play Population Publishing Radiation Injuries Radiation exposure Radiation therapy Receptor Protein-Tyrosine Kinases Recovery Reserve Stem Cell Rodent Model Role Secretory Cell Signal Transduction Supporting Cell Testing cellular targeting chemotherapy cytokine design epithelial stem cell epithelium regeneration in vitro Model in vivo inflammatory disease of the intestine injury recovery intestinal crypt intestinal epithelium intestinal homeostasis neuregulin-4 notch protein novel radiation effect radiation response receptor regeneration following injury repaired side effect stem cell biomarkers stem cell niche stem cell population stem cell replacement stem cell self renewal stem cells therapeutic target villin

项目摘要

PROJECT SUMMARY The receptor tyrosine kinases ErbB4 and ErbB3 can protect intestinal enterocytes from apoptosis, but their potential roles in inducing stem cell regeneration after an insult—arguably of equal importance in the face of challenge—are not known. Here, we aim to define the function of ErbB3 and ErbB4 in post-injury recovery of intestinal stem cells, and thus in regeneration of the epithelium. ErbB4 expression is high in regenerating enteroids, and the ErbB4 ligand NRG4 promotes crypt plating efficiency. ErbB4-null enteroid cultures have a compromised intestinal stem cell niche with loss of the rapidly-cycling stem cell marker Lgr5 and reduced Paneth cell numbers. Similar to ErbB4, ErbB3 promotes enterocyte survival, but unlike ErbB4 it suppresses secretory cell differentiation; for example, ErbB3-null enteroids have an expanded Paneth cell census. Thus, the two neuregulin receptors seem to play complementary but distinct roles in regulating renewal and development in the crypt. Preliminary data suggest that both of these receptors are induced during recovery from injury models in vitro and in vivo, and loss of either perturbs recovery. We will build on our published and preliminary data to test the hypothesis that signaling through ErbB4 and ErbB3 promotes balanced regeneration of the intestinal epithelium after injury. We will (1) define the impact of ErbB4 or ErbB3 loss or activation on intestinal epithelial regeneration after injury, (2) determine the molecular mechanisms linking ErbB4 and ErbB3 to intestinal stem cell regeneration, especially connections to the fundamental regulators of stem cell self-renewal, Wnt and Notch. These studies will advance basic understanding of how intestinal stem cells and the stem cell niche are repaired, as well as identify novel regulatory mechanisms that could be future therapeutic targets to drive intestinal regeneration after injury.

项目概要受体酪氨酸激酶 ErbB4 和 ErbB3 可以保护肠细胞免受细胞凋亡，但它们在损伤后诱导干细胞再生方面的潜在作用——可以说是面对挑战时的同等重要性——尚不清楚。在这里，我们的目标是定义该函数。 ErbB3 和 ErbB4 在肠道干细胞损伤后恢复中的作用，从而在肠道干细胞的再生中发挥作用 ErbB4 在再生肠样细胞中高表达，ErbB4 配体 NRG4 促进隐窝铺板效率 ErbB4 无效肠样培养物的肠道受损。快速循环干细胞标记物 Lgr5 缺失和潘氏细胞减少的干细胞生态位与 ErbB4 类似，ErbB3 促进肠细胞存活，但与 ErbB4 不同的是，它抑制肠细胞存活。分泌细胞分化；例如，ErbB3 缺失的类肠细胞具有扩张的潘氏细胞因此，这两种神经调节蛋白受体似乎在人口普查中发挥着互补但不同的作用。初步数据表明，这两者都在调节地穴的更新和发展。受体在体外和体内损伤模型恢复过程中被诱导，并且任一受体的丧失我们将根据已发布的初步数据来检验这一假设。通过 ErbB4 和 ErbB3 的信号传导促进肠道的平衡再生我们将 (1) 定义 ErbB4 或 ErbB3 丢失或激活对上皮细胞的影响。损伤后肠上皮再生，（2）确定连接的分子机制 ErbB4 和 ErbB3 与肠道干细胞再生，特别是与基础的联系干细胞自我更新的调节因子、Wnt 和 Notch 这些研究将推进基础研究。了解肠道干细胞和干细胞生态位如何修复，以及确定新的调节机制，这些机制可能成为未来驱动肠道的治疗靶点受伤后的再生。