THE ROLE OF ALPHA-DEFENSINS IN CYSTIC FIBROSIS LUNG DISE

作为K23项目的主要研究者，我将于1999年6月在佛罗里达大学完成儿科肺病学的奖学金培训。 我已接受了同一部门的一个教师职位，自1999年7月起生效。 除了住院医师和加速临床和研究奖学金培训外，我还完成了3年的基础和应用科学全职研究，我的近期职业目标是继续接受旨在将生物医学研究的调查结果转化为临床有用应用的方法学培训。 拟议的培训计划包括早期的相关教学培训和研究工作的启动，并在3年的指导研究在80%的努力达到高潮。 在这个为期5年的培训计划中获得的技能和经验将为独立的进一步研究和资助提供机会。 这项研究旨在描述中性粒细胞或α-防御素在囊性纤维化（CF）肺病中的作用。 我们的初步数据表明，与健康志愿者相比，CF患者气道中的α-防御素水平显著升高。 这些肽具有细胞毒性和炎症特性，并可能在CF的慢性支气管内感染中发挥作用。 使用支气管镜评估肺部和支气管肺泡灌洗，我们计划确定α-防御素在CF肺病中的特异性和净效应。我们还计划探索用雾化的α 1-抗胰蛋白酶调节α-防御素有害作用的可能性，α 1-抗胰蛋白酶是一种在CF肺病中可能具有广泛治疗特性的分子。 该项目的方法多种多样，包括患者选择和招募、研究性支气管镜检查和标本处理、免费离体测定和实验、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。 结构化的教学培训将补充这一项目，提供多学科培训，以实现独立进行面向病人的研究。 在完成这项培训和研究后，我的长期职业兴趣将继续留在儿科患者中嗜中性粒细胞介导的肺部疾病的发病机制和应用临床干预领域。

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.