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综合征（BOS）。研究表明，免疫介导的损伤和气道上皮细胞的丧失对于BOS的发病机理至关重要。因此，针对这种生物学可以为制定新的治疗策略提供一个重大突破，以防止肺移植中排斥。我们已经确定了循环上皮祖细胞（CEPC），这些细胞被募集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，这是气道中祖细胞基底上皮细胞的标记，以及通过CXCR4/CXCL12生物轴的交通。与CEPC在气道修复中的重要性一致，以中和对CXCL12的抗体阻止CEPC的募集导致鳞状化生的表型。这意味着气道利基市场中循环和常驻祖细胞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，在肺移植后增强受体CEPC植入供体气道上皮的植入将改善上皮修复，从而减少对供体肺的同种识别，并最终减少BOS。该提案的目的是：1）研究居民和循环上皮祖细胞群体在BOS发展中的作用，通过选择性消除这些细胞群体，2）检查CEPC的动员增强对BOS的发展对BOS发展的影响和3）使用患者肺部血液样本，以确定CEPC与患者相关。拟议的研究将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。公共卫生相关性：成年干细胞对肺部修复有很大的希望，我们发现血液中的成年干细胞有助于修复肺部。许多终末期肺部疾病患者进行肺移植，但与许多并发症有关。我们假设在肺移植后动员成年干细胞将改善受伤的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。