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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54HL096458-10
Application #
8527824
Study Section
Special Emphasis Panel (ZRG1-HOP-Y (50))
Program Officer
Banks-Schlegel, Susan P
Project Start
2004-08-06
Project End
2014-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
10
Fiscal Year
2013
Total Cost
$1,190,000
Indirect Cost
$214,229
Name
University of North Carolina Chapel Hill
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Bustamante-Marin, Ximena M; Ostrowski, Lawrence E (2016) Cilia and Mucociliary Clearance. Cold Spring Harb Perspect Biol :
Knowles, Michael R; Zariwala, Maimoona; Leigh, Margaret (2016) Primary Ciliary Dyskinesia. Clin Chest Med 37:449-61
Horani, Amjad; Ferkol, Thomas W (2016) Primary ciliary dyskinesia and associated sensory ciliopathies. Expert Rev Respir Med 10:569-76
Shapiro, Adam J; Zariwala, Maimoona A; Ferkol, Thomas et al. (2016) Diagnosis, monitoring, and treatment of primary ciliary dyskinesia: PCD foundation consensus recommendations based on state of the art review. Pediatr Pulmonol 51:115-32
Polineni, Deepika; Davis, Stephanie D; Dell, Sharon D (2016) Treatment recommendations in Primary Ciliary Dyskinesia. Paediatr Respir Rev 18:39-45
Milla, Carlos E (2016) The evolving spectrum of ciliopathies and respiratory disease. Curr Opin Pediatr 28:339-47
Merkel, Peter A; Manion, Michele; Gopal-Srivastava, Rashmi et al. (2016) The partnership of patient advocacy groups and clinical investigators in the rare diseases clinical research network. Orphanet J Rare Dis 11:66
Dell, Sharon D; Leigh, Margaret W; Lucas, Jane S et al. (2016) Primary Ciliary Dyskinesia: First Health-related Quality-of-Life Measures for Pediatric Patients. Ann Am Thorac Soc 13:1726-1735
Horani, Amjad; Ferkol, Thomas W; Dutcher, Susan K et al. (2016) Genetics and biology of primary ciliary dyskinesia. Paediatr Respir Rev 18:18-24
Leigh, Margaret W; Ferkol, Thomas W; Davis, Stephanie D et al. (2016) Clinical Features and Associated Likelihood of Primary Ciliary Dyskinesia in Children and Adolescents. Ann Am Thorac Soc 13:1305-13

Showing the most recent 10 out of 51 publications