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.

项目摘要 嗅上皮细胞（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续存在和维持功能 在成人组织中。老年人感觉功能的下降伴随着神经系统的病理变化， OE出现是因为正常活跃的嗅觉干细胞和祖细胞，即球状基底细胞， 细胞（GBC）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（HBC），尽管GBC的神经源性衰竭和消失，但仍处于休眠状态; 相反，如果OE被嗅觉毒素损伤，HBC激活并有助于修复 上皮一种治疗策略，其实现了HBC在环境中的可控活化， 耗尽的OE可能是治疗年龄相关嗅觉功能障碍的最佳方法。我们有 证明了转录因子p63是调节HBC激活的主开关， p63水平的急剧下降对于活化是必要的和充分的。此外，Notch 1的信号传导 维持p63水平并抑制激活;我们假设Notch 1的配体表达Jagged 1 因为它们的选择性死亡足以激活HBCs。我们在此提出两个目标 应用程序建立在以前的进步。目标1关注Notch信号传导，并询问Notch信号传导是如何精确地 OE中Notch途径的复杂性调节HBCs？其他问题涉及其他信号 从猪细胞中提取来调节HBCs。最后，我们将扩展操纵Notch信号的研究 在人类HBCs的组织培养中。目标2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HBCs中蛋白水平的下降？ 完成后，我们将对负担沉重国家的进程有更透彻的了解， 从休眠状态中被转移出来，这样它们可能有助于上皮再生。这种理解 在老鼠和人类中，遗传操纵都提供了深刻的分析能力， 推进我们旨在确定缓解嗅觉感觉功能障碍的治疗策略的努力， 特别是伴随衰老的感官丧失。