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

嗅觉上皮水平基底细胞激活的分子调控

基本信息

批准号：
9886978
负责人：
JAMES E. SCHWOB
金额：
$ 67.03万
依托单位：
TUFTS UNIVERSITY BOSTON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-07 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9886978
关键词：
Ablation Address Adult Affect Afferent Neurons Age Aging Anosmia Area Back Basal Cell Biopsy Cause of Death Cell Culture Techniques Cell Proliferation Cell physiology Cells Cessation of life Data Disease Elderly Epithelial Epithelium Excision Fostering Functional disorder Gene Expression Genes Goals Gold Health Human In Situ In Vitro Injury Intranasal Administration Knock-out Lesion Life Ligands Mission Molecular Multipotent Stem Cells Mus NOTCH1 gene National Institute on Deafness and Other Communication Disorders Natural regeneration Nose Notch Signaling Pathway Nutritional status Olfactory Epithelium Pathologic Pathway interactions Play Population Positioning Attribute Process Proteins Proteolysis Quality of life Recovery Regulation Reserve Stem Cell Resort Rodent Role Safety Sensory Signal Pathway Signal Transduction Smell Perception Supporting Cell System Testing Therapeutic Tissues Transactivation Transplantation Treatment Efficacy Ubiquitin age related aged cell type conditional knockout epithelial injury epithelium regeneration exhaust exhaustion extracellular falls gene repression genetic manipulation in vivo inhibitor/antagonist knockout gene multicatalytic endopeptidase complex neurogenesis notch protein olfactory sensory neurons receptor repaired response selective expression stem cells sustentacular cell therapeutic target tissue culture tissue stem cells transcription factor

项目摘要

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.

项目概要嗅觉上皮 (OE) 补充嗅觉感觉神经元数量的能力损伤后上皮的再生取决于干细胞的持久性和维持功能老年人感觉功能的下降伴随着病理变化。由于正常活跃的嗅觉干细胞和祖细胞（即球状基底细胞）而出现的 OE 在这种情况下，储备干细胞（GBC）变得紊乱并最终耗尽。尽管神经源性耗竭和 GBC 消失，水平基底细胞 (HBC) 仍然处于休眠状态；相反，如果 OE 被嗅毒素损坏，HBC 就会激活并有助于修复在上皮细胞环境中实现 HBC 可控激活的治疗策略。疲惫的嗅觉可能是治疗与年龄相关的嗅觉功能障碍的最佳方法。转录因子 p63 是调节 HBC 激活的主开关 – p63 水平的急剧下降对于激活来说是必要且充分的。维持 p63 水平并抑制激活；我们勇敢地说 Notch1 的配体是 Jagged1 表达的由于它们的选择性死亡足以激活 HBC，因此我们提出了 2 个目标。应用程序以先前的进展为基础，目标 1 重点关注 Notch 信号，并询问如何精确地实现这一点。 OE 中 Notch 通路的复杂性调节 HBC 有其他问题吗？最后，我们将扩展我们操纵 Notch 信号传导的研究。目标 2 关注损伤后的激活过程，并询问如何进行。 p63 的蛋白酶体降解会导致小鼠和人类 HBC 中蛋白质水平的下降吗？完成后，我们将对 HBC 的过程有更彻底的了解。摆脱休眠状态，以便它们可能有助于上皮再生。两种小鼠的机制，其中基因操作提供了深刻的分析能力，并且在人类中也会我们的努力旨在确定缓解嗅觉感觉功能障碍的先进治疗策略，尤其是随着衰老而出现的感觉丧失。