Progenitor Cells in Airway Repair

气道修复中的祖细胞

• 批准号: 8318148
• 负责人: BRIGITTE N GOMPERTS
• 金额: $ 38.12万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8318148
• 关键词: Acute; Allografting; Biological; Biology; Blood; Blood Circulation; Blood specimen; Bronchiolitis Obliterans; CXCL12 gene; CXCR4 gene; Cells; Chronic; Cytokeratin; Data; Development; Engraftment; Epithelial; Epithelial Cells; Epithelium; Excision; Functional disorder; Goals; Human Characteristics; Immune; Immunosuppression; Injury; Lung; Lung Transplantation; Lung diseases; Mediating; Messenger RNA; Modeling; Morbidity - disease rate; Mus; Outcome; Pathogenesis; Patients; Phenotype; Population; Pre-Clinical Model; Prevalence; Principal Investigator; Recruitment Activity; Regimen; Role; Sampling; Squamous Metaplasia; Staging; Stem cells; Syndrome; Testing; Therapeutic; Transgenic Organisms; Transplant Recipients; Transplantation; abstracting; adult stem cell; airway epithelium; diphtheria toxin receptor; improved; injured; injured airway; insight; lung allograft; lung repair; mortality; mouse model; neutralizing antibody; novel therapeutics; pre-clinical; prevent; progenitor; programs; repaired; trafficking

Project Summary/Abstract: Lung transplantation is often the only viable therapeutic option for end-stage pulmonary disorders. Unfortunately, lung transplantation is associated with numerous serious complications including acute rejection and bronchiolitis obliterans syndrome (BOS). Studies have indicated that immune-mediated injury and loss of airway epithelial cells is critical in the pathogenesis of BOS. Targeting this biology could therefore provide a major breakthrough for developing new therapeutic strategies for preventing rejection in lung transplantation. We have identified circulating epithelial progenitor cells (CEPC) that are recruited to the injured airway and aid in repair of the epithelium. These cells express cytokeratin 5, a marker of progenitor basal epithelial cells in the airway, and traffic via the CXCR4/CXCL12 biological axis. Consistent with the importance of CEPC in airway repair, blocking the recruitment of CEPC with neutralizing antibodies to CXCL12 resulted in the phenotype of squamous metaplasia. This implies that the interaction between circulating and resident progenitor epithelial cells in the airway niche is critical for normal airway repair. We hypothesize that enhancing engraftment of recipient CEPC into donor airway epithelium after lung transplantation will improve epithelial repair, result in less allo-recognition of the donor lung and ultimately reduce BOS. The goal of this proposal is to: 1) investigate the role of resident and circulating epithelial progenitor cell populations in the development of BOS by selectively eliminating these cell populations, 2) examine the effect of enhanced mobilization of CEPC on the development of BOS and 3) use patient lung transplant blood samples to determine whether CEPC correlate with patient outcome. The proposed studies will allow us to further understanding of the role of epithelial progenitor cells in the airway and will enable the harnessing of the therapeutic potential of CEPC.

项目摘要/摘要： 肺移植通常是终末期肺部疾病的唯一可行的治疗选择。 不幸的是，肺移植与许多严重的并发症有关，包括急性 排斥和支气管炎闭塞性综合征（BOS）。研究表明免疫介导 气道上皮细胞的损伤和损失对于BOS的发病机理至关重要。针对这种生物学可以 因此，为制定新的治疗策略提供了一个重大突破 在肺移植中。我们已经确定了被募集的循环上皮祖细胞（CEPC） 到受伤的气道并有助于修复上皮。这些细胞表达细胞角蛋白5，一个标记 气道中的祖细胞基础上皮细胞，以及通过CXCR4/CXCL12生物轴的交通。 与CEPC在气道维修中的重要性一致，阻止了CEPC的招募 对CXCL12的中和抗体导致鳞状化生的表型。这意味着这一点 气道小众中循环和居民祖细胞上皮细胞之间的相互作用对于 正常气道维修。我们假设将接收者CEPC植入供体气道 肺移植后上皮将改善上皮修复，从而减少对同种识别 供体肺，最终减少BOS。该提议的目的是：1）调查居民的作用 和通过选择性消除BOS的开发中循环上皮祖细胞群 这些细胞种群，2）检查CEPC动员增强对发展的影响 BOS和3）使用患者肺移植血液样本来确定CEPC是否与患者相关 结果。拟议的研究将使我们能够进一步了解上皮祖细胞的作用 气道中的细胞，将实现CEPC的治疗潜力。