Pathogenesis of PCD Lung Disease

University Of North Carolina Chapel Hill, Chapel Hill NC

Investigators

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Abstract

DESCRIPTION (provided by applicant): An important component of lung defense is the efficiency of mucociliary clearance (MCC). Primary ciliary dyskinesia (PCD) is a human genetic model of abnormal ciliary function and defective MCC. The overall goals of this project are to relate the molecular etiology of PCD to the ciliary phenotype (ultra structure; ciliary beat frequency and pattern). We hypothesize that certain abnormalities in ciliary ultra structure (particularly defective outer and inner dynein arms) reflect genetic mutations, and that discrete groups of genes encode each of those structures. Moreover, we hypothesize that mutations in genes encoding for outer dynein arm versus inner dynein arm proteins will be associated with different effects on ciliary beat frequency and waveform. Finally, we hypothesize that we will discover disease-causing mutations in PCD by a candidate gene approach, focused on genes encoding proteins in the dynein arms and central complex. To test our hypotheses, we have accumulated a cohort (n=86) of PCD patients who fulfill rigorous diagnostic criteria. In these (and an additional 60) PCD patients, we will determine ciliary ultra structure by transmission electron microscopy (TEM) and functional phenotype of PCD cilia using high-speed video-microscopy techniques. The strategy to test for disease-causing genetic mutations in PCD will use several different approaches, including an approach to narrow the search for candidate genes by using intra-genic polymorphisms, to test for "linkage" (exclusion mapping) within individual families. Taken together, these studies will allow us to determine correlations between ciliary ultra structure/function and genotype. Ultimately, we will develop a better understanding of the pathogenesis of airway disease resulting from abnormal ciliary function and defective mucociliary clearance. From a broader perspective, the identification of the genetic basis of PCD in patients with known ultrastructural defects will later provide the opportunity to test for "milder" genetic forms of ciliary dysfunction that predispose to more common airways diseases.