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

• 批准号: 10554436
• 负责人: JAMES E. SCHWOB
• 金额: $ 62.6万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 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/10554436
• 关键词: Ablation; Acceleration; Address; Adult; Affect; Afferent Neurons; Age; Aging; Anosmia; Area; Back; Basal Cell; Biopsy; Cause of Death; Cell Proliferation; Cell physiology; Cells; Cessation of life; Data; Deterioration; Disease; Elderly; Engraftment; Epithelium; Excision; Fostering; Functional disorder; Gene Expression; Genes; Goals; Health; Human; In Situ; In Vitro; Injury; Intranasal Administration; Knock-out; Lesion; Life; Ligands; Messenger RNA; 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; Olfactory dysfunction; Pathologic; Pathway interactions; Population; Positioning Attribute; Process; Proteins; Proteolysis; Quality of life; Recovery; Regulation; Reserve Stem Cell; Resort; Rodent; 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; epithelial repair; epithelium regeneration; exhaust; exhaustion; extracellular; falls; gene repression; genetic manipulation; in vivo; inhibitor; knockout gene; multicatalytic endopeptidase complex; neurogenesis; notch protein; olfactory sensory neurons; receptor; response; restraint; stem; stem cell function; stem cells; sustentacular cell; therapeutic target; tissue culture; tissue stem cells; transcription factor

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 在该成人组织内。老年人感觉功能下降，伴随着以下病理变化： 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 细胞（GBC）变得紊乱并最终耗尽。在这种情况下，储备干细胞，即 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 上皮。一种在特定环境下实现 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。我们有 证明转录因子 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。此外，Notch1 发出信号 维持 p63 水平并抑制激活；我们假设Notch1的配体是Jagged1表达的 由维持​​细胞产生，因为它们的选择性死亡足以激活 HBC。我们在此提出 2 个目标 应用程序建立在以前的进步的基础上。目标 1 重点关注 Notch 信号传导，并询问如何精确地执行 OE 中 Notch 通路的复杂性调节 HBC？其他问题涉及其他信号 源自 Sus 细胞来调节 HBC。最后，我们将扩展操纵 Notch 信号传导的研究 在组织培养中转化为人类 HBC。目标 2 重点关注受伤后的激活过程，并询问如何 p63 的蛋白酶体降解导致小鼠和人类 HBC 中蛋白质水平下降？ 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。这种理解 小鼠和人类的机制，其中基因操作提供了深刻的分析能力 推进我们的努力，旨在确定缓解嗅觉感觉功能障碍的治疗策略， 尤其是随着衰老而出现的感觉丧失。