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.

项目总结/文摘: