Therapeutic potential for modulation of olfactory basal stem cells

嗅觉基底干细胞调节的治疗潜力

基本信息

批准号：
10429978
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
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-15 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10429978
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 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 therapy 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 translational applications translational potential treatment strategy

项目摘要

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.

项目概要/摘要据估计，至少 12% 的人口受到嗅觉丧失的影响。嗅觉丧失，嗅觉丧失功能障碍，可能是由于衰老、既往感染或受伤造成的，目前尚无有效的治疗方法。虽然病因可能有所不同，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。成人嗅觉神经发生的调节因此，这是一个活跃的研究领域。以最近允许纯化和培养的成功为基础成体嗅觉基底干细胞或祖细胞（球形基底细胞）的鉴定，以及 Polycomb 的鉴定嗅细胞亚群中的复合物，该提案询问 Polycomb 复合物是否以及如何介导表观遗传修饰影响嗅觉上皮的神经发生和上皮稳态。多梳复合物是发育过程中重要的表观遗传调节因子，但它们在嗅觉中的作用维护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，Aim1 将检验该假设 Polycomb 复合物调节嗅觉上皮的更新和分化。除了定义基底细胞的表观遗传调控，Aim2将测试基底干细胞用于修复嗅觉的能力损害。该目标将解决一个主要的转化问题：基于细胞的疗法能否治疗感音神经性疾病？嗅觉丧失？因为再生宿主神经元会干扰术后功能恢复的评估针对小鼠嗅觉损伤，我们将采用一种新型的诱导性嗅觉丧失小鼠模型，其中再生神经元缺乏纤毛，用于测试移植细胞的治疗潜力。实验将结合组织学、电生理学和行为方法全面评估基底细胞植入诱导性嗅觉丧失宿主。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。这些研究以当前缺乏治疗的重要临床问题为指导，将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，将为设计感音神经细胞疗法提供必要的数据继发于损伤或神经源性疲劳的嗅觉丧失，例如老花症。