The Molecular Regulation of Horizontal Basal Cell Activation in the Olfactory Epithelium

项目总结 嗅觉上皮(OE)补充嗅觉神经元数量的能力和 损伤后上皮的再生依赖于干细胞的持久性和维持功能 在那个成人组织里。老年人的感觉功能下降伴随着病理变化 因为正常活跃的嗅干和祖细胞，即球状基底细胞而出现的OE 细胞(GBCs)，变得无序并最终耗尽。在这种情况下，储备干细胞，即 水平基底细胞(HBCs)，尽管神经源性疲惫和消失，但仍处于休眠状态； 相反，如果嗅觉毒素损伤了OE，HbCs就会激活，并有助于修复 上皮组织。一种可控制激活Hbcs的治疗策略 精疲力竭的OE可能是治疗与年龄相关的嗅觉功能障碍的最佳方法。我们有 证实转录因子p63是调节HBc激活的主开关-a P63水平的急剧下降是激活所必需的，也是充分的。此外，Notch1的信令 维持p63水平并抑制激活；我们假设Notch1的配体Jagged1表达 通过支持细胞，因为它们的选择性死亡足以激活HBCs。我们在这方面提出了两个目标 申请在以前进展的基础上再接再厉。目标1专注于Notch信令，并询问如何准确地 OE中Notch途径调控HBCs的复杂性？其他问题涉及到其他信号 从Sus细胞衍生出来的调节Hbcs的物质。最后，我们将扩展我们对操纵Notch信令的研究 人HBCs的组织培养。目标2侧重于受伤后的激活过程，并询问如何 P63蛋白酶体降解导致小鼠和人HbCs的蛋白质水平下降？ 完成后，我们将对重债穷国的进程有一个更加透彻的了解。 被转移出休眠状态，因此它们可能有助于上皮再生。对这个概念的理解 在小鼠和人类身上，基因操作都能提供深刻的分析能力 推进我们旨在确定减轻嗅觉障碍的治疗策略的努力， 尤其是随着年龄的增长而导致的感觉丧失。

PROJECT SUMMARY The capacity of the olfactory epithelium (OE) for replenishing the population of olfactory sensory neurons and for regenerating the epithelium after injury depends on the persistence and maintained function of stem cells within that adult tissue. Decline in sensory function in the elderly is accompanied by pathological changes in the OE that emerge because the normally active olfactory stem and progenitor cells, namely globose basal cells (GBCs), become disordered and eventually depleted. In this setting, the reserve stem cells, namely the horizontal basal cells (HBCs), remain dormant despite the neurogenic exhaustion and disappearance of GBCs; in contrast, if the OE is damaged by an olfactotoxin, the HBCs activate and contribute to the repair of the epithelium. A therapeutic strategy that accomplishes controllable activation of HBCs in the setting of an exhausted OE offers possibly the best approach to treating age-related olfactory dysfunction. We have demonstrated that the transcription factor p63 is the master switch that regulates HBC activation – a precipitous decline in p63 levels is necessary and sufficient for activation. Further, signaling by Notch1 maintains p63 levels and restrains activation; we hypothesize that the ligand for Notch1 is Jagged1 expressed by sustentacular cells, since their selective death is sufficient to activate HBCs. We propose 2 Aims in this application to build on previous advances. Aim 1 focuses on Notch signaling and asks how precisely do the complexities of the Notch pathway in the OE regulate HBCs? Additional questions address the other signals that derive from Sus cells to regulate HBCs. Finally, we will extend our studies manipulating Notch signaling in tissue culture to human HBCs. Aim 2 focuses on the activation process following injury and asks how does proteasomal degradation of p63 contribute to the decline in protein levels in mouse and in human HBCs? When completed, we will have achieved a much more thorough understanding of the process by which HBCs are shifted out of dormancy so that they might contribute to epithelial regeneration. That understanding of mechanism in both mouse, where genetic manipulations offer profound analytic power, and in humans will advance our efforts aimed at identifying therapeutic strategies for alleviating olfactory sensory dysfunction, particularly the sensory loss which accompanies aging.