Genetic Disorders of Mucociliary Clearance

摘要 遗传性疾病的粘液纤毛清除协会包括八个地理上不同的临床 北美各地的研究中心，共同研究与受损的 粘膜纤毛清除和气道宿主防御，导致慢性化脓性呼吸道疾病。骗局- 在推进临床实践、开发诊断测试和验证 原发性睫状体运动障碍的各种临床结果测量。此外，该财团是关键， 40个主要纤毛运动障碍相关基因的鉴定和表征， 疾病病理生理学和揭示基因型-表型关系。通过这些调查， 我们最近已经确定了已确诊或可能诊断为原发性免疫缺陷的受试者。 通过系统地评估患者，再加上基因检测，我们希望确定分子诊断， 慢性化脓性呼吸道疾病患者的诊断。 这项多学科建议的首要目标是确定遗传基础、病理生理学和 罕见的慢性化脓性呼吸道疾病的临床表现;提高诊断能力;以及 为临床试验确定新的治疗靶点和终点，最终改善受影响患者的结局 个体该计划包括三个不同但主题相关的项目。第一个项目是一个跨sec- 定义慢性化脓性肺病和支气管炎的遗传和病理生理基础的国家研究- 扩张，集中在原发性纤毛运动障碍和原发性免疫缺陷。第二，我们将启动一个 一项纵向研究，旨在评估呼吸恶化对原发性高血压患者疾病进展的影响， 玛丽纤毛运动障碍。最后，第三个项目是一项横断面研究， 原发性纤毛运动障碍和原发性免疫缺陷的上气道和耳部疾病。 该联盟还将开发试点和可行性项目，以产生新的诊断方法 原发性纤毛运动障碍和原发性免疫缺陷，提供了对罕见的过敏性紫癜发病机制的见解， 肺疾病，并测试新的结果的措施，临床试验准备的关键。联合体将 通过职业提升核心支持参与罕见疾病研究的早期职业研究者， 提供培训、研讨会和跨联盟的交流。此外，我们将开发独特的教育 与世界各地的专业协会和研究合作伙伴的项目。 最终，我们希望该联盟的努力将大大促进我们对遗传学、病理生理学和遗传学的理解。 ogy，临床表现，和各种慢性化脓性呼吸道疾病的自然史，改善 诊断工具和管理，并产生新的治疗目标和临床试验的终点。

ABSTRACT The Genetic Disorders of Mucociliary Clearance Consortium consists of eight geographically diverse clinical research sites across North America that collectively study inherited respiratory diseases related to impaired mucociliary clearance and airway host defense, resulting in chronic suppurative respiratory diseases. The Con- sortium has made remarkable progress advancing clinical practice, developing diagnostic tests and validating various clinical outcome measures for primary ciliary dyskinesia. In addition, the Consortium was pivotal to the identification and characterization of 40 primary ciliary dyskinesia-associated genes, which has provided insights into disease pathophysiology and uncovered genotype-phenotype relationships. Through these investigations, we have recently identified subjects who have confirmed or probable diagnosis of primary immunodeficiencies. By systematically evaluating patients, coupled with genetic testing, we expect to determine the molecular diag- nosis in patients with chronic suppurative respiratory disease. The overarching goal of this multidisciplinary proposal is to determine the genetic bases, pathophysiology and clinical manifestations of rare, chronic suppurative respiratory diseases; improve diagnostic capabilities; and identify novel therapeutic targets and endpoints for clinical trials that will ultimately improve outcomes for affected individuals. The program includes three distinct but thematically-linked projects. The first project is a cross-sec- tional study defining the genetic and pathophysiological bases of chronic suppurative lung disease and bronchi- ectasis, concentrating on primary ciliary dyskinesia and primary immunodeficiencies. Second, we will initiate a longitudinal study to assess the effect of respiratory exacerbations on disease progression in patients with pri- mary ciliary dyskinesia. Finally, the third project is a cross-sectional study characterizing the clinical impact of upper airway and ear disease in primary ciliary dyskinesia and primary immunodeficiencies. The Consortium will also develop pilot and feasibility projects that will yield novel approaches to diagnosing primary ciliary dyskinesia and primary immunodeficiencies, provide insights into pathogenesis of rare suppura- tive lung diseases, and test novel outcome measures critical for clinical trial readiness. The Consortium will support early-career investigators involved in rare disease research through the Career Enhancement Core, providing training, workshops, and exchanges across consortia. In addition, we will develop unique educational programs with professional societies and research collaboratives worldwide. Ultimately, we expect the Consortium's efforts will greatly advance our understanding of genetics, pathophysiol- ogy, clinical manifestations, and the natural history of various chronic suppurative respiratory diseases, improve diagnostic tools and management, and yield novel therapeutic targets and endpoints for clinical trials.