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 嗅觉上皮（OE）的能力补充嗅觉感觉神经元和 损伤后再生上皮取决于干细胞的持久性和维持功能 在那个成年组织中。老年人的感觉功能下降是通过病理变化来实现的 出现的OE是因为正常活跃的嗅觉茎和祖细胞，即Globoso碱 细胞（GBC），变得无序并最终耗尽。在这种情况下，储备干细胞，即 尽管神经源性疲惫和GBC消失，但水平基线细胞（HBC）仍然休眠。 相比之下，如果OE被橄榄毒素损坏，HBC会激活并有助于修复 上皮。一种治疗策略，可以在设置中完成HBC的受控激活 疲惫的OE提供了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 - A p63水平的急剧下降是必要的，足以激活。此外，Notch1发出信号 保持p63水平并限制激活；我们假设Notch1的配体锯齿状1表示 通过静脉细胞，由于其选择性死亡足以激活HBC。我们提出2的目标 申请以先前的进步为基础。 AIM 1专注于Notch信号，并询问如何精确 OE中Notch途径的复杂性调节HBCS？其他问题涉及其他信号 从SUS细胞衍生以调节HBC。最后，我们将扩展我们的研究操纵Notch信号传导 在人类HBC的组织培养中。 AIM 2专注于受伤后的激活过程，并询问如何如何 p63的蛋白酶体降解有助于小鼠和人HBC中蛋白质水平的下降？ 完成后，我们将对HBCS的过程进行更透彻的了解 从休眠状态转移到了上皮再生中。对 两种小鼠的机制，遗传操作都具有深刻的分析能力，在人类中将 促进我们的努力旨在确定减轻嗅觉感觉障碍的治疗策略， 特别是涉及衰老的感觉损失。