This Consortium of 7 clinical research sites will continue to study rare diseases of the airways that are associated with defective mucociliary clearance. These disorders involve chronic airways infection with resultant bronchiectasis. Over the past 4 years, this Consortium has made great progress in studies of variant CF, Primary Ciliary Dyskinesia (PCD), and pseudohypoaldosteronism. Major advances include: 1) improved diagnostic testing in PCD (nasal NO as screening test and development of clinical genetic tests);2) discovery of novel phenotypes (increased prevalence of heterotaxy and congenital heart disease reflecting mutations in PCD-causing genes), and 3) identification of novel therapeutic targets in PCD (many STOP mutations in PCD-causing genes, which could potentially be corrected by a novel small molecule, PTC124). In the next 5 years, this Consortium will complete two ongoing longitudinal studies in PCD infants, children, and adolescents, which are designed to determine the age of onset and rate of progression of lung disease, onset of respiratory infection and evolution of respiratory microbiology, and to help define outcome measures for interventional trials. The diagnostic protocol will be extended to include 300 patients with non- CF (""""""""idiopathic"""""""") bronchiectasis, which will likely lead to identification of a variety of rare disorders, including PCD, immunodeficiency, and a1-antitrypsin deficiency. Patients with rare airway disorders frequently have sub-optimal treatment, because diagnosis is incorrect (or delayed), and treatment is not driven by evidence based medicine. The three key hypotheses of this proposal are that: 1) systematic evaluation of patients with rare airways diseases will yield more precise diagnoses, and lead to better diagnostics, including genetic testing;2) well-designed cross-sectional and longitudinal studies will provide insight into disease pathogenesis that will direct development of Clinical Practice Guidelines for these disorders;and 3)longitudinal studies and pilot projects will define outcome measures for future therapeutic studies in PCD. Taken together, the proposed work will lead to earlier diagnoses, improved care, and more effective therapeutic interventions for rare airway diseases. In the broader view, better definition of pathobiology and/or molecular etiologies of these disorders will enhance our understanding of normal airway defense mechanisms.
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