A key component of lung defense is the efficiency of mucociliary clearance (MCC). Primary ciliary dyskinesia (PCD) is a human genetic disorder with defective MCC. This ongoing project is designed to identify additional disease-causing mutations in PCD, and correlate the molecular etiologies with the ciliary phenotype (ultrastructure, wave form and beat frequency). We have recently shown that the normal human cilium has a distinctive waveform, i.e. beats in- plane with defined curvatures and amplitudes for the effective (forward) and recovery stroke. We hypothesize that discrete sets of genes contribute to the structure and function of the ciliary outer dynein arm (ODA), inner dynein arm (IDA), and central pair (CP) and radial spoke (RS) complex (CP/RS), and that we can identify novel genetic mutations in different structural components of the cilium that will have different effects on ciliary ultrastructure, wave-form, and beat frequency. Importantly, we are now able to identify patients with PCD who do not have hallmark diagnostic ultrastructural defects, based on distinctive clinical phenotypes (including situs inversus), low or borderline nasal NO production, and abnormal ciliary motility. Identification of PCD patients with normal ciliary ultrastructure (~16% of PCD patients at UNC) offers the opportunity to discover mutations in genes that cause functional, but not ultrastructural, defects (such as DNAH11), and to correlate those mutations with ciliary waveform abnormalities. Over the past 4 years, we have made great progress in identifying mutations in 2 genes (DNAI1 and DNAH5) that cause ~60% of ODA defects in PCD, and ~35% of PCD overall. We will extend our search for disease-causing mutations in PCD, using several different approaches, including studies of additional candidate genes, (guided by ultrastructure), plus insights from ciliary proteomics, and family-based studies. Taken together, these studies will provide new insights regarding the relationship of mutations in specific genes to ciliary ultrastructural and functional defects. These studies will not only greatly enhance our ability to diagnose PCD, but will also lead to discovery of "milder" genetic mutations associated with normal ciliary ultrastructure, and likely some residual ciliary function. Ultimately, this will allow future studies of the role of partial loss of ciliary function in the predisposition to more common airways diseases, such as chronic bronchitis and chronic obstructive pulmonary disease.

Public Health Relevance

The overall short-term goals of this project are to 1) study genes that are key to the function of respiratory cilia to protect the normal lung, and 2) define the effects of adverse genetic mutations that reduce the effectiveness of ciliary function and mucociliary clearance, and cause Primary Ciliary Dyskinesia (PCD), which results in life-shortening lung disease. The long-term goal of this project is to develop better understanding of the underlying genetic variability that adversely affects ciliary function, and predisposes to common airway diseases, such as asthma and chronic obstructive pulmonary disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL071798-07
Application #
8011707
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Banks-Schlegel, Susan P
Project Start
2002-12-01
Project End
2012-12-31
Budget Start
2011-01-01
Budget End
2011-12-31
Support Year
7
Fiscal Year
2011
Total Cost
$386,927
Indirect Cost
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
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
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
Davis, Stephanie D; Ferkol, Thomas W; Rosenfeld, Margaret et al. (2015) Clinical features of childhood primary ciliary dyskinesia by genotype and ultrastructural phenotype. Am J Respir Crit Care Med 191:316-24
Marshall, Christian R; Scherer, Stephen W; Zariwala, Maimoona A et al. (2015) Whole-Exome Sequencing and Targeted Copy Number Analysis in Primary Ciliary Dyskinesia. G3 (Bethesda) 5:1775-81
Szymanski, Eva P; Leung, Janice M; Fowler, Cedar J et al. (2015) Pulmonary Nontuberculous Mycobacterial Infection. A Multisystem, Multigenic Disease. Am J Respir Crit Care Med 192:618-28
Shapiro, Adam J; Tolleson-Rinehart, Sue; Zariwala, Maimoona A et al. (2015) The prevalence of clinical features associated with primary ciliary dyskinesia in a heterotaxy population: results of a web-based survey. Cardiol Young 25:752-9
Sears, Patrick R; Yin, Wei-Ning; Ostrowski, Lawrence E (2015) Continuous mucociliary transport by primary human airway epithelial cells in vitro. Am J Physiol Lung Cell Mol Physiol 309:L99-108
Fedick, Anastasia M; Jalas, Chaim; Treff, Nathan R et al. (2015) Carrier frequencies of eleven mutations in eight genes associated with primary ciliary dyskinesia in the Ashkenazi Jewish population. Mol Genet Genomic Med 3:137-42

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