STRUCTURE AND ORGANIZATION OF HUMAN CILIA IN NORMAL AND DISEASE STATES

University Of Colorado, Boulder CO

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Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Primary ciliary dyskinesia (PCD) is a disease in which a mutation in one of the approximately 250 proteins that make up a human cilium causes a defect in ciliary function. This defect, in turn, results in impaired or absent mucociliary clearance, and leads to chronic infection of the airways and sinuses. Other tissues containing motile cilia/flagella can also be affected. PCD is difficult to diagnose, and it is likely that many people with PCD are still not being identified and consequently, not receiving proper treatment. Currently, the standard method for diagnosing PCD relies heavily on subjective evaluation of transmission electron micrographs of cross-sections of cilia to identify missing axonemal structures (e.g., dynein arms). Even though the techniques for imaging biological structures have advanced tremendously, the methods used for diagnosis of PCD have not changed in any substantial way since the first description of the disease. More surprisingly, although sophisticated techniques such as computer averaging of multiple images and 3-D tomograms are being applied to the analysis of simple biological systems, e.g., flagella from Chlamydomonas, these same procedures have not yet been applied to human material. This is primarily due to the lack of suitable human samples. However, we now have the ability to produce sufficient quantities of highly purified human ciliary axonemes for analysis. This project will therefore focus on applying the most advanced procedures for imaging and analysis to human ciliary axonemes to determine the structure of this important organelle at higher resolution. Further, we propose to analyze samples from PCD patients as they become available to gain a better understanding of the structural abnormalities that accompany this condition and gain insight into how these alterations may affect both the diagnosis of disease and the disease pathology.