Genetic Disorders of Mucociliary Clearance

描述（由申请人提供）：本申请的总体目标是在北卡罗来纳大学（UNC）建立一个罕见疾病临床研究中心（RDCRC），以及地理上分散的气道研究中心（arc）的相关网络，以研究气道的罕见疾病。这4个研究中心（北卡大学、华盛顿大学圣路易斯分校、科罗拉多大学丹佛分校和华盛顿大学西雅图分校）将合作开展粘纤毛清除遗传缺陷患者的诊断、遗传和其他研究，特别是原发性纤毛运动障碍（PCD）、变型囊性纤维化（CF）和假性醛固酮减少症（PHA）。患有这些发病率和死亡率增加的不寻常疾病的患者往往诊断延迟（或不正确），因为诊断测试不容易获得。这一应用的两个中心假设是：1)对这些患者进行广泛、系统的诊断评估将产生更精确的诊断标准和更好的诊断技术，包括基因检测；2)采用最先进的方法和严格的横断面和纵向研究设计对这些患者的特定队列进行系统评估，将更好地了解这些疾病的临床发病机制。在一项对300名PCD患者进行的为期5年的纵向研究中，我们将使用创新技术，包括测量婴儿胸部pft和hrct，以确定PCD患者肺部疾病的早期发病和进展。此外，10个地理位置分散的地点将作为PCD临床中心，以协助纵向研究中PCD患者的随访护理。这种合作将通过定义PCD的临床实践指南来改善护理。我们在PCD方面的试点项目旨在开发更好的诊断工具和生物标志物，表征呼吸病理生物学，评估新的治疗药物，并开发PCD的筛选测试。我们将把罕见呼吸道疾病的培训项目扩展到北卡罗来纳大学的成熟和年轻的研究人员，以及其他地方的研究人员。最后，我们会与DTCC合作，协调和扩展现有的网站，为公众、病人和医疗专业人员提供教育、转介和招募研究对象的信息。

DESCRIPTION (provided by applicant): The overall goal of this application is to establish a Rare Disease Clinical Research Center (RDCRC) at the University of North Carolina (UNC), and an associated Network of geographically-dispersed Airways Research Centers (ARCs), to study rare diseases of the airways. These 4 sites (UNC; Washington Univ., St. Louis; Univ. of Colorado, Denver; and Univ. of Washington, Seattle) will collaborate in diagnostic, genetic, and other studies in patients with genetic impairments in mucociliary clearance, specifically primary ciliary dyskinesia (PCD), variant forms of cystic fibrosis (CF), and pseudohypoaldosteronism (PHA). Patients with these unusual disorders with increased morbidity and mortality often have delayed (or incorrect) diagnoses, because diagnostic tests are not readily available. The two central hypotheses of this application are that: 1) a broad-based, systematic approach to the diagnostic evaluation of these patients will yield more precise diagnostic criteria and better diagnostic techniques, including genetic testing; and 2) systematic evaluation of specific cohorts of these patients with state-of-the-art methodologies and rigorous cross-sectional and longitudinal study designs will provide better understanding of the clinical pathogenesis of these disorders. In a five-year longitudinal study of 300 patients with PCD, we will use innovative techniques, including measurement of PFTs and HRCTs of the chest in infants, to define early onset and progression of pulmonary disease in PCD. In addition, 10 geographically-dispersed sites will serve as PCD Clinical Centers, to assist in the follow-up care of PCD patients in the longitudinal study. This collaborative effort will improve care by defining clinical practice guidelines for PCD. Our Pilot projects in PCD are designed to develop better diagnostic tools and biomarkers, characterize the respiratory pathobiology, evaluate novel therapeutic agents, and develop screening tests for PCD. We will extend our training programs in rare airways diseases to established and young investigators at UNC, and to investigators at other sites. Finally, we will work with the DTCC to coordinate and expand current websites to provide information to the lay public, patients, and medical professionals for education, referral, and recruitment of study subjects.