PATHOGENESIS OF CF AND PCD LUNG DISEASE

本临床研究项目的目的是增加对非哮喘呼吸道疾病分子、细胞和器官水平发病机制的了解，从而更好地诊断和治疗肺部疾病。黏液纤毛器是正常呼吸道宿主防御的主要组成部分，它依赖于呼吸道上皮细胞对呼吸道表面液体离子成分和体积的调节以及纤毛结构和功能的整合。囊性纤维化(CF)和原发性睫状肌运动障碍(PCD)是肺部疾病的两种遗传模型，可导致呼吸道清除异常和慢性肺部疾病。研究项目分为两大部分。具体目的I将在分子、细胞和临床水平上确定突变的CFTR与肺部疾病表达的关系。在具体目标二中，工作重点将是确定与PCD相关的遗传突变，包括严格量化和定义PCD中不同的细胞生物学和纤毛超微结构表型，以便能够通过候选基因方法进行初步测试。这些研究目标将在人类受试者临床研究职业发展的整体背景下进行，重点是最初几年对课程工作的资助和与CF相关的项目的完成。未来几年的资金将集中在PCD的研究上。因此，这项研究将把人类研究的实践经验与遗传学、分子生物学技术、生物统计学、临床研究设计和负责任的人类研究行为的课程相结合。这项工作将由一名资深临床研究人员导师监督。还将通过与各种领域的专家合作提供培训，包括分子生物学、临床遗传学、电生理学和细胞生物学。北卡罗来纳大学教堂山分校的环境为这一临床研究事业的发展提供了丰富的资源，提供正规课程，以及各种以患者为导向的研究领域的专家。这一奖项将极大地增强申请者未来进行独立、高质量临床研究的能力。

The goal of this clinical research project is to increase the understanding of the molecular, cellular, and organ-level pathogenesis of non-asthmatic airways disease, which will lead to better diagnosis and treatment of lung disease. The mucociliary apparatus is a major component of normal airway host defense, which depends on the integration of airway epithelial regulation of ion composition and volume of airway surface liquid, and ciliary structure and fiinction. Cystic fibrosis (CF) and primary ciliary dyskinesia (PCD) are two genetic models of lung disease, which lead to abnormal airway clearance and chronic lung disease. The research project is sub-divided into two major components. Specific Aim I will define the relationship between mutant CFTR and expression of lung disease at a molecular, cellular and clinical level. In specific aim II, work will focus on defining the genetic mutations associated with PCD, including rigorous quantitation and definition of different cell biologic and ciliary ultrastructural phenotypes in PCD, to allow testing initially via the candidate gene approach. These research goals will be undertaken in the overall context of career development for clinical research in human subjects, with emphasis in the initial years of funding on course work and completion of the projects related to CF. Later years of funding will concentrate on the research in PCD. Thus, the research will combine practical experience in human research with coursework in genetics, molecular biology techniques, biostatistics, clinical study design, and the responsible conduct of human research. The work will be supervised by a senior clinical investigator mentor. Training will also be provided by collaboration with experts in a variety of fields, including molecular biology, clinical genetics, electrophysiology, and cell biology. The environment at UNC-Chapel Hill is rich in resources for this clinical research career development, offering formal courses, and experts in a variety of patient-oriented research fields. This award will greatly enhance the future ability of the applicant to conduct independent, high-quality clinical research.