Our research is concerned with the cell biology of cilia and flagella, including the non-motile primary cilia present on most cells in our body and believed to be “cell antennae” involved in sensory reception and transduction. Our findings have important implications for male infertility, and for diseases of the lung, kidney and eye, all of which contain cilia.

In many of these studies we are using the unicellular Chlamydomonas, a model flagellated organism amenable to biochemical, genetic and molecular genetic approaches.   One area of research involves the outer dynein arm of the flagellar axoneme (Fig. 1), which is the best characterized of all dyneins and serves as the paradigm for this large class of molecular motors.   This research includes 1) characterization of a newly discovered complex that is necessary for the outer dynein arm to bind to the flagellar microtubules, and 2) study of several still uncharacterized genes known to be necessary for outer arm assembly.  The human homologues of these genes are candidates for causing primary ciliary dyskinesia, a human disease in which the outer dynein arms are frequently missing.

We also are studying a process, called “intraflagellar transport” (IFT), which involves the active movement of multi-subunit protein particles from the base to the tip of the cilium or flagellum, and back to the base again (Fig. 2).  These particles carry cargo necessary for assembly and maintenance of the cilium or flagellum, and also may be transporting signals from the cilium or flagellum to the cell body and vice versa.  We are characterizing both the motors responsible for this transport, and the individual polypeptides that make up the IFT particles.  Because IFT is essential for the assembly of all cilia and flagella, disruption of IFT-particle protein genes blocks assembly of cilia, providing a powerful tool for studying the function of primary cilia in the kidney, eye, and elsewhere.

Finally, we have recently completed a proteomic analysis of the Chlamydomonas flagellum.  This has resulted in a virtual “gold mine” of data that will form the basis for many exciting projects.  Because the proteins of cilia and flagella have been highly conserved throughout evolution, the human homologues of most of these proteins are readily identified.  This opens the door to understanding the functions of many previously uncharacterized proteins.  We currently are investigating the functions of some of the most interesting proteins using reverse genetics approaches in Chlamydomonas.  Defects in some of the homologues are known to cause disease in mice and humans, suggesting that these diseases are due to defects in cilia.

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