Coordination and Force Transmission of Beating Cilia

About This Grant

Cilia are tiny, slender structures that extend out from cells lining fluid-filled passages. In our bodies, cilia are present in the lungs, brain, and reproductive systems. These cilia beat back and forth with a wave-like motion that moves fluid along the passages. Failure of cilia beating can lead to severe health problems such as lung infections, brain swelling, or infertility. Cilia are also found on many single-celled organisms, in which cilia beating propels the organism through surrounding fluid. In both the human body and swimming cells, cilia beating must be coordinated to be effective. This project will support research that studies how coordination of cilia is maintained in the single-celled organism, Tetrahymena. How changing fluid resistance and altering connections between cilia changes the coordination of cilia beating and affects swimming speed will be studied. This research intends to help understand and potentially treat diseases related to cilia defects. Understanding cilia coordination could also lead to new designs of man-made systems to move fluid or propel objects using multiple coordinated wave generators. This project will also support workforce development through research, education, and outreach. The PIs will train graduate students at the interface of mechanics, biophysics and cell biology, involve undergraduates in summer research and independent study projects during the academic year, and engage K-12 students with hands-on activities to introduce design and problem-solving concepts. Motile cilia are powered by the “9+2” axoneme, an array of nine microtubule doublets surrounding a central pair of singlet microtubules, connected by a network of passive spokes and links and driven by dynein motor proteins. At the base of the cilium, the basal body (BB) is an array of microtubule triplets anchored to the cell cortex by microtubule bundles (post-ciliary and transverse) and connected to each other via striated fibers. Force transmission between BBs and the cell cortex to reveal how these interactions modulate ciliary beating and coordination will be studied. The first aim is to measure dynamic deformations of BBs in Tetrahymena, using expansion microscopy and super-resolution imaging, and uncover how BB deformations are affected by ciliary beating and intracellular connections. The second aim is to quantify metachronal coordination of Tetrahymena cilia and test the role of connecting fibers in controlling the waveform and timing of cilia beating. Laser ablation will be used to disrupt connections between adjacent cilia and quantify the effects on cilia waveform and coordination. The third aim is to model and simulate the mechanics of cilia beating in Tetrahymena. Two types of computer models will be built: (1) the Axoneme-BB model will be a detailed structural model of the ciliary cytoskeleton and its connections to the cell; (2) the Cilia Array model will be a coarse-grained model of multiple cilia that each exhibit autonomous oscillations, that includes intracellular coupling to mediate metachronal coordination. Comparison of model predictions to experimental measurements will clarify the role of intracellular force transmission in cilia coordination. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.