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.

项目总结