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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.

项目总结/文摘