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：
9901504
负责人：
Mark R Frey
金额：
$ 42.21万
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/9901504
关键词：
Acute Apoptosis CD3 Antigens Cell Count Cell Differentiation process Cells Censuses Chronic Data Development Enterocytes Epithelial Epithelial Cells Epithelium 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 cell regeneration 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 repaired self-renewal side effect stem cell niche stem cell population 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.

项目摘要受体酪氨酸激酶ERBB4和ERBB3可以保护肠肠上皮细胞免受凋亡，但它们在受伤后的诱导干细胞再生中的潜在作用 - 可以面对挑战的同等重要性 - 不知道。在这里，我们旨在定义功能 ERBB3和ERBB4在肠道干细胞的伤害后恢复中上皮。 ERBB4的表达在再生肠todi中很高，ERBB4配体NRG4 促进加密电镀效率。 Erbb4-null Enteroid培养物的肠道受损干细胞小众，损失了快速循环的干细胞标记LGR5并减少了Paneth细胞数字。与ERBB4相似，ERBB3促进肠球菌的生存，但与ERBB4不同，它抑制了秘书细胞分化；例如，ERBB3无效的肠todotoids具有扩展的paneth细胞人口普查。那两个神经蛋白接收器似乎在调节地下室的更新和发展。初步数据表明这两个在体外和体内从损伤模型中恢复期间诱导受体，并丧失任何一个 Perturbs恢复。我们将基于我们已发布的初步数据来检验假设通过ERBB4和ERBB3发出信号会促进肠道的平衡再生受伤后上皮。我们将（1）定义ERBB4或ERBB3损失或激活对损伤后肠上皮再生，（2）确定连接的分子机制 ERBB4和ERBB3到肠道干细胞再生，尤其是与基本的连接干细胞自我更新，Wnt和Notch的调节剂。这些研究将提高基本了解如何修复肠道干细胞和干细胞生态位确定可能是未来的治疗靶标的新型调节机制受伤后再生。