THE ROLE OF ALPHA-DEFENSINS IN CYSTIC FIBROSIS LUNG DISE

作为这项K23提案的首席研究员，我将于1999年6月在佛罗里达大学完成儿科肺病学的研究员培训。我已经接受了同一部门的教员职位，从1999年7月起生效。在完成了三年的基础和应用科学全日制研究以及住院医师培训和加速临床和研究奖学金培训后，我近期的职业目标是继续接受方法学方面的进一步培训，以将生物医学研究的调查结果转化为临床有用的应用。拟议的培训计划包括早期相关的教学培训和研究工作的启动，并以三年80%的努力进行指导研究为最终结果。在这个为期5年的培训计划中获得的技能和经验将为进一步的研究和独立提供资金提供机会。这项拟议的研究旨在确定中性粒细胞或α-防御素在囊性纤维化(CF)肺部疾病中的作用。我们的初步数据显示，与健康志愿者相比，慢性阻塞性肺疾病患者呼吸道中的α-防御素水平显著升高。这些多肽具有细胞毒性和炎症特性，可能在慢性支气管炎的发生发展中起一定作用。通过支气管镜对肺部和支气管肺泡灌洗的评估，我们计划确定α-防御素在慢性萎缩性肺病中的特异性和净效应。我们还计划探索雾化α-抗类型蛋白对α-防御素的有害作用进行调节的可能性，该分子可能具有治疗慢性肺病的广泛特性。该项目的方法是多样化的，包括患者选择和招募、研究支气管镜检查和标本处理、免费的体外分析和实验、临床数据收集、临床试验设计和管理以及广泛的统计分析方法。结构化教学培训将补充这一项目，提供多学科培训，旨在独立指导以患者为中心的研究。在完成这项培训和研究后，我的长期职业兴趣将保持在儿童患者中性粒细胞介导的肺部疾病的发病机制和应用临床干预方面。

As the principal investigator of this K23 proposal, I will complete fellowship training in pediatric pulmonology at the University of Florida in June 1999. I have accepted a faculty position in the same division effective in July 1999. Having completed 3 years of full-time research in basic and applied sciences in addition to residency and accelerated clinical and research fellowship training, my immediate career goals are to pursue further training in methodology designed to translate investigative findings of biomedical research to clinically useful applications. The proposed training program consists of an early period of relevant didactic training and initiation of research efforts, and culminates in 3 years of mentored research at 80 percent effort. The skills and experience obtained during this 5 year training program will provide opportunities for further research and funding in an independent manner. The proposed research is designed to characterize the role of neutrophil or alpha-defensins in cystic fibrosis (CF) lung disease. Our preliminary data indicates that alpha-defensin levels are significantly elevated in the airways of CF patients compared to healthy volunteers. These peptides possess cytotoxic and inflammatory properties, and may play a role in chronic endobronchial infection in CF. Using bronchoscopic evaluation of the lungs and bronchoalveolar lavage, we plan to define the specific and net effect of alpha-defensins in CF lung disease. We also plan to explore the possibility of modulation of deleterious effects of alpha-defensin with aerosolized alpha1- antitypsin, a molecule that may possess a wide range of therapeutic properties in CF lung disease. The methodology of this project is diverse, consisting of patient selection and recruitment, research bronchoscopy and specimen processing, complimentary ex vivo assays and experiments, collection of clinical data, clinical trial design and administration, and a broad range of statistical analysis methods. Structured didactic training will complement this project in providing multidisciplinary training geared towards independence in the conductance of patient-oriented research. Following completion of this training and research, my long-term career interest will remain in the area of pathogenesis and applied clinical intervention of neutrophil-mediated pulmonary disease in pediatric patients.