Progenitor Cells in Airway Repair

气道修复中的祖细胞

• 批准号: 7568010
• 负责人: BRIGITTE N GOMPERTS
• 金额: $ 38.5万
• 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 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7568010
• 关键词: Acute; Allografting; Biological; Biology; Blood; Blood Circulation; Blood specimen; Bronchiolitis Obliterans; CXCL12 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; Role; Sampling; Squamous Metaplasia; Staging; Stem cells; Syndrome; Testing; Therapeutic; Transgenic Organisms; Transplant Recipients; Transplantation; Treatment Protocols; adult stem cell; airway epithelium; diphtheria toxin receptor; improved; injured; injured airway; insight; lung allograft; mortality; mouse model; neutralizing antibody; novel therapeutics; pre-clinical; prevent; progenitor; programs; public health relevance; repaired; trafficking

DESCRIPTION (provided by applicant): 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 further understanding of the role of epithelial progenitor cells in the airway and will enable the harnessing of the therapeutic potential of CEPC. PUBLIC HEALTH RELEVANCE: Adult stem cells hold great promise for repair of the lungs and we have discovered adult stem cells in the blood that contribute to repair of the lungs. Lung transplants are performed for many patients with end stage lung diseases, but are associated with many complications. We hypothesize that mobilizing adult stem cells after lung transplantation will improve the repair of the injured donor lungs and reduce the complications of lung transplantation. We plan to test this hypothesis in preclinical models and in lung transplant patient samples.

描述（由申请人提供）：肺移植通常是终末期肺部疾病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相关，包括急性排斥反应和闭塞性细支气管炎综合征（BOS）。研究表明，免疫介导的气道上皮细胞损伤和损失在 BOS 的发病机制中至关重要。因此，针对这种生物学特性可以为开发预防肺移植排斥反应的新治疗策略提供重大突破。我们已经鉴定出循环上皮祖细胞（CEPC），它们被募集到受损气道并帮助修复上皮。这些细胞表达细胞角蛋白 5，这是气道中基底上皮祖细胞的标志物，并通过 CXCR4/CXCL12 生物轴进行交通。与 CEPC 在气道修复中的重要性一致，用 CXCL12 中和抗体阻断 CEPC 的募集会导致鳞状上皮化生的表型。这意味着气道微环境中循环和常驻祖上皮细胞之间的相互作用对于正常气道修复至关重要。我们假设肺移植后增强受体CEPC植入供体气道上皮将改善上皮修复，导致供体肺的同种异体识别减少并最终降低BOS。该提案的目标是：1) 通过选择性消除常驻和循环上皮祖细胞群在 BOS 发展中的作用，2) 检查增强 CEPC 动员对 BOS 发展的影响，3) 使用患者肺移植血样来确定 CEPC 是否与患者预后相关。拟议的研究将有助于进一步了解上皮祖细胞在气道中的作用，并能够利用 CEPC 的治疗潜力。公共健康相关性：成体干细胞对于肺部修复具有巨大的希望，我们已经在血液中发现了有助于肺部修复的成体干细胞。许多患有终末期肺病的患者都会进行肺移植，但肺移植会带来许多并发症。我们假设肺移植后动员成体干细胞将改善受损供体肺的修复并减少肺移植的并发症。我们计划在临床前模型和肺移植患者样本中检验这一假设。