Genetic Disorders of Mucociliary Clearance

摘要 黏液纤毛清除联合体遗传性疾病由8个不同地理位置的临床病例组成 北美各地共同研究与受损相关的遗传性呼吸道疾病的研究网站 粘液纤毛清除和呼吸道宿主防御，导致慢性化脓性呼吸道疾病。Con-- 在推进临床实践、开发诊断测试和验证方面取得了显著进展 原发性睫状肌运动障碍的各种临床结局指标。此外，该财团对 40个原发睫状肌运动障碍相关基因的鉴定和特征 疾病病理生理学和未被覆盖的基因-表型关系。通过这些调查， 我们最近确定了已确诊或可能诊断为原发免疫缺陷的受试者。 通过系统地评估患者，再加上基因测试，我们希望确定分子诊断。 慢性化脓性呼吸道疾病患者的临床表现。 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目标和终点，最终改善受影响患者的结果 个人。该计划包括三个不同但有主题联系的项目。第一个项目是跨秒- 确定慢性化脓性肺病和支气管病的遗传和病理生理基础的全国性研究 扩张，集中于原发纤毛运动障碍和原发免疫缺陷。第二，我们将启动一个 评估呼吸加重对慢性阻塞性肺疾病患者疾病进展影响的纵向研究 玛丽纤毛运动障碍。最后，第三个项目是一项横断面研究，描述了阿司匹林的临床影响 原发性纤毛运动障碍和原发免疫缺陷的上呼吸道和耳部疾病。 该联盟还将开发试点和可行性项目，以产生新的诊断方法 原发纤毛运动障碍和原发免疫缺陷，为罕见紫癜性疾病的发病机制提供了洞察力。 活动性肺部疾病，以及对临床试验准备至关重要的测试新结果衡量标准。该财团将 通过职业提升核心支持参与罕见疾病研究的职业早期研究人员， 提供培训、研讨会和跨财团交流。此外，我们还将发展独特的教育 与世界各地的专业协会和研究合作组织合作的项目。 最终，我们预计该联盟的努力将极大地促进我们对遗传学、病理生理学- 改善各种慢性化脓性呼吸道疾病的病史、临床表现和自然病史 诊断工具和管理，并为临床试验产生新的治疗靶点和终点。

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.