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

项目摘要 受体酪氨酸激酶ErbB 4和ErbB 3可以保护肠上皮细胞免受 细胞凋亡，但它们在诱导干细胞再生后的潜在作用， 同样重要的是，面对挑战，我们还不知道。在这里，我们的目标是定义函数 ErbB 3和ErbB 4在肠干细胞损伤后恢复中的作用， 上皮细胞ErbB 4在再生肠样组织中表达较高，ErbB 4配体NRG 4 促进隐窝铺板效率。ErbB 4缺失的肠样培养物具有受损的肠上皮细胞， 干细胞龛，快速循环干细胞标志物Lgr 5缺失，潘氏细胞减少 号码与ErbB 4类似，ErbB 3促进肠上皮细胞存活，但与ErbB 4不同，它抑制肠上皮细胞的存活。 分泌细胞分化;例如，ErbB 3缺失的类肠细胞具有扩张的潘氏细胞 人口普查因此，这两种神经调节蛋白受体似乎在细胞内起着互补但不同的作用。 调节地穴的更新和发展。初步数据显示，这两个 受体在体外和体内损伤模型恢复期间被诱导， 干扰恢复。我们将建立在我们公布的和初步的数据，以测试假设 通过ErbB 4和ErbB 3的信号传导促进肠道的平衡再生， 损伤后的上皮。我们将（1）定义ErbB 4或ErbB 3缺失或激活对 肠上皮损伤后的再生;（2）确定其分子机制 ErbB 4和ErbB 3对肠干细胞再生的影响，特别是与基础细胞的连接。 干细胞自我更新的调节因子Wnt和Notch。这些研究将推动基础 了解肠道干细胞和干细胞龛是如何修复的，以及 确定新的调节机制，可能是未来的治疗目标，以推动肠道 损伤后的再生

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.