Therapeutic potential for modulation of olfactory basal stem cells

嗅觉基底干细胞调节的治疗潜力

• 批准号: 10176446
• 负责人: Bradley J Goldstein
• 金额: $ 34.21万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10176446
• 关键词: Address; Adult; Affect; Aging; Anosmia; Area; BMI1 gene; Basal Cell; Behavioral; Biological Assay; Cell Culture Techniques; Cell Therapy; Cell physiology; Cells; Chromatin; Chromosomes; Cilia; Clinical; Clinical Trials; Colony-Forming Units Assay; Complex; DNA sequencing; Data; Data Set; Development; Disease; EZH2 gene; Elderly; Electrophysiology (science); Engraftment; Epigenetic Process; Epithelial; Etiology; FDA approved; Failure; Gene Expression; Genetic; Goals; Histology; Homeostasis; Human; Immunoprecipitation; In Vitro; Infection; Injury; Lesion; Maintenance; Mediating; Modeling; Modification; Mus; National Health and Nutrition Examination Survey; National Institute on Deafness and Other Communication Disorders; Natural regeneration; Neurons; Nose; Odors; Olfactory Basal Cell; Olfactory Epithelial Cell; Olfactory Epithelium; Olfactory Pathways; Olfactory dysfunction; Orthologous Gene; PRC1 Protein; Patients; Pattern; Peripheral Blood Stem Cell; Pharmaceutical Preparations; Physiology; Polycomb; Population; Property; Proteins; Publishing; Recovery; Recovery of Function; Regenerative Medicine; Regulation; Reporting; Research; Role; Secondary to; Sensory; Smell Perception; Taste Perception; Techniques; Testing; Therapeutic; Tissue Sample; Transplantation; Variant; Work; base; chromatin modification; conditional knockout; design; effective therapy; embryonic stem cell; epigenetic regulation; exhaustion; experimental study; functional restoration; genome-wide; improved; in vivo; inhibitor/antagonist; innovation; knock-down; mouse model; neurogenesis; novel; olfactory disorder; olfactory neurogenesis; overexpression; pluripotency; preservation; prevent; regeneration potential; repaired; restoration; self-renewal; stem cell engraftment; stem cells; success; therapeutic evaluation; treatment strategy

PROJECT SUMMARY/ABSTRACT It is estimated that at least 12% of the population is affected by olfactory loss. Anosmia, the loss of olfactory function, can be due to aging, prior infection, or injury, and there are currently no effective treatments. Although etiologies may vary, evidence suggests that neurogenic exhaustion, or a failure to replace or maintain the olfactory neuron population, underlies many olfactory disorders. The regulation of adult olfactory neurogenesis is, therefore, an area of active research. Building upon recent successes permitting the purification and culture of adult olfactory basal stem or progenitor cells (globose basal cells), and the identification of Polycomb complexes in subsets of olfactory cells, this proposal asks whether and how Polycomb complex-mediated epigenetic modifications influence neurogenesis and epithelial homeostasis in the olfactory epithelium. Polycomb complexes are essential epigenetic regulators during development, but their roles in olfactory maintenance and renewal have not been investigated. Using a culture model, chromosome immunoprecipitation- DNA sequencing (ChIP-seq), as well as in vivo approaches, Aim1 will test the hypothesis that Polycomb complexes regulate renewal and differentiation in the olfactory epithelium. In addition to defining epigenetic regulation in basal cells, Aim2 will test the ability of basal stem cells to be used to repair olfactory damage. This Aim will address a major translational question: can a cell-based therapy treat a sensorineural anosmia? Because regenerating host neurons interfere with the assessment of functional recovery following olfactory lesions in mice, we will employ a novel inducible anosmia mouse model, in which regenerating neurons lack cilia, for testing therapeutic potential of engrafted cells. The experiments will combine histology, electrophysiology and behavioral approaches to comprehensively evaluate basal cell engraftment into inducible anosmia hosts. Also, this model will be used to directly test the effects of altering Polycomb expression in donor cells. These studies, guided by important clinical problems lacking current treatments, will use innovative multi-pronged approaches to define previously unexplored mechanistic controls of olfactory renewal and differentiation, and will provide essential data to design cell-based therapy for sensorineural olfactory losses secondary to damage or neurogenic exhaustion, such as presbyosmia.

项目总结/摘要 据估计，至少有12%的人口受到嗅觉丧失的影响。嗅觉缺失，嗅觉丧失 功能，可能是由于老化，先前的感染或损伤，目前没有有效的治疗方法。虽然 病因可能各不相同，有证据表明，神经源性衰竭，或未能更换或维持 嗅觉神经元群体，是许多嗅觉障碍的基础。成人嗅神经发生的调控 是一个活跃的研究领域。在最近成功的基础上， 成年嗅基底干细胞或祖细胞（球状基底细胞）的分化，以及Polycomb的鉴定 复合物的嗅觉细胞亚群，这个建议问是否以及如何Polycomb复合物介导的 表观遗传修饰影响嗅上皮中的神经发生和上皮稳态。 多梳复合体是发育过程中必不可少的表观遗传调节因子，但它们在嗅觉中的作用， 维修和更新尚未进行调查。使用培养模型，染色体 免疫沉淀- DNA测序（ChIP-seq），以及体内方法，Aim 1将测试假设 Polycomb复合物调节嗅上皮的更新和分化。除了定义 Aim 2将测试基底干细胞用于修复嗅觉的能力， 损害这个目标将解决一个主要的翻译问题：基于细胞的治疗可以治疗感觉神经性疾病吗？ 嗅觉缺失？因为再生的宿主神经元干扰了对功能恢复的评估， 在小鼠嗅觉损伤中，我们将采用一种新的诱导性嗅觉丧失小鼠模型， 神经元缺乏纤毛，用于测试移植细胞的治疗潜力。实验将结合联合收割机组织学， 电生理学和行为学方法来全面评估基底细胞移植到 诱导型嗅觉丧失宿主此外，该模型将用于直接测试改变Polycomb的效果 在供体细胞中表达。这些研究以目前缺乏治疗的重要临床问题为指导， 使用创新的多管齐下的方法来定义以前未探索的嗅觉机械控制 更新和分化，并将提供必要的数据，以设计基于细胞的治疗感觉神经 继发于损伤或神经源性衰竭的嗅觉丧失，如老年嗅觉症。