Functional, Structural, and Genetic Characterization of Pediatric Ciliopathies
Thomas W. Ferkol, M.D.
Center for Pediatric Pulmonary Disease
Large-Scale Interdisciplinary Research Initiative
7/1/2008 - 6/30/2012
Susan Dutcher, Philip Bayly, Steven L. Brody
With each breath, the human lung is exposed to inhaled bacteria, pollutants, and other airborne particulates. Complex, local defenses have evolved to protect the bronchi, including the mucociliary escalator, which mechanically eliminates bacteria that deposit at the airway surface. Cilia are essential, specialized cellular structures, composed of hundreds of structural proteins, and play critical roles in clearance of inhaled foreign materials from the lung.
Dysfunction of cilia and related structures, flagella, is known or suspected in a number of genetic and acquired disorders (ciliopathies), including primary ciliary dyskinesia, chronic lung disease, persistent ear infections, heart malformations and other birth defects. The ultimate goal of this project is to discover new genetic mutations involved in cilia-related human disease by studying patients with known primary ciliary dyskinesia, and populations enriched with this disease, and model the genetic and functional defects in a simple flagellated organism (algae) to allow us to understand the relationship between specific gene products and cilia (flagellar) motion. Our approach is highly generalizable and applicable to other inherited (and possibly even acquired) ciliopathies. Indeed, the proposed project will illuminate the causes of these conditions and allow us to define genotype-phenotype relationships in affected individuals.