Cilia are highly conserved organelles found on nearly every differentiated cell and play vital motile and signaling roles in the adult human body and during development. There are 2 main classes of cilia, motile and immotile (primary) cilia. The motile cilia are used for both sensory and motile functions, whereas the primary cilia are strictly sensory in function. Ciliary organelles protrude from the surface of cells and consist of the ciliary membrane, a specialized extension of the plasma membrane, and an internal cytoskeletal structure composed of microtubules, called the axoneme. The movement of motile cilia is generated by the microtubule motor called dynein. Within the motile cilium, there are several classes of dynein motors that contribute to motility, which are anchored in a precise pattern along the length of the axonemal microtubules. This collection of dynein motors must be assembled in the cell body, transported into cilia and then docked, or anchored, to their precise position. Moreover, the dynein motors must be exquisitely regulated in a coordinated manner to generate complex ciliary bends and precise ciliary beat frequencies. Key cilia cytoskeletal structures involved in regulation of ciliary motility include the central pair (CP), radial spokes (RS) and nexin links (now called the nexin-dynein regulatory complex). These structures anchor highly conserved signaling molecules that function to transmit mechanochemical signals from the central pair to the dynein arm motors.
My lab uses Chlamydomonas reinhardtii, a unicellular, green alga with 2 cilia that are used for locomotion, to determine the molecular mechanisms for assembly, targeting and regulation of the axonemal dynein motors. Chlamydomonas offers exceptional experimental advantages for the study of cilia and the dynein motors that drive their movement, including genetic, ultrastructural, molecular and biochemical approaches.
Importantly, genetic defects (gene mutations) or acquired defects (excessive alcohol consumption) affecting cilia, and the ciliary dyneins motors, can lead to a wide range of diseases and syndromes called “the ciliopathies”. Cilia dysfunction results in widespread pathologies in fetal development and function of nearly every organ system in the adult body. Recently, we have been utilizing Chlamydomonas to determine the ciliary targets of alcohol exposure. Chronic alcohol consumption in humans leads to airway cilia dysfunction resulting in compromised mucociliary clearance leading to recurring lung infections. Our recent work has demonstrated that alcohol (ethanol) exposure reduces ciliary beat frequencies by targeting the outer dynein arm (ODA) ciliary motor. In addition, we are pursuing studies focused on determining the molecular mechanisms for targeting docking and regulation of the inner and outer dynein arm motors.
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