Collaborative Research: Mathematical, Numerical, and Experimental Investigation of Flow Sensing by the Primary Cilium

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This interdisciplinary team of three investigators will integrate mathematical modeling, numerical simulations, and experiments to investigate key fundamental issues surrounding the mechanosensory roles of primary cilia. Primary cilia are solitary (one per cell), immotile, antenna-like microtubule-based organelles extending from the surface of nearly every mammalian cell. Mechanical stimuli (such as blood flow) cause deflection of the primary cilium, initiating downstream signaling cascades to the rest of the cell. Defects in primary cilia have been associated with atherosclerosis, osteoporosis, and cancer. Yet the biochemical signaling pathways from primary cilia bending to cellular responses remain a complex and unsolved problem that will be addressed by the three PIs. Results from the proposed research will further our understanding of subcellular mechanosensing of primary cilia, and will lay the foundation for designing therapeutic strategies to treat various human diseases due to defected primary cilia. The PIs will engage both undergraduate and graduate students to conduct interdisciplinary research, and results from the proposed research can provide new approaches in mathematical biology, biophysics, biomedical engineering and medicine. The methods and techniques to be developed in this project will go beyond the context of primary cilia and extend to other problems featuring mechanically induced cellular functions, for example, in the regulation of vascular tone. Long speculated to trigger intracellular calcium release as a second messenger for subsequent cellular biochemical signaling and responses (such as change in patterns of cytoskeleton or altered ion and solvent transport), recent experiments using genetically-coded calcium indicators refuted the calcium-responsiveness of primary cilia for a range of cells. Thus it is imperative to establish fundamental understanding of the role of primary cilia in subcellular mechanosensing. One main challenge to identify the pathway(s) from cilium bending to subsequent bio-chemical signaling is to isolate primary cilium contribution from the rest of the cell responding directly to the same mechanical stimuli. By using an optical trap, PI Resnick is able to bend a single primary cilium without exerting force on the rest of the cell, thus providing a great opportunity for insight to the missing pathways. Combining this experimental technique with mathematical modeling (PI Young) and numerical simulations (PI Peng), the team aims to (1) characterize the mechanical properties of the primary cilium, (2) qualify the coupling between cilium and cytoskeleton, and (3) identify the time scales and characteristics of signaling activation to quantify ciliary-mediated flow sensing. Results from these three aims will advance the mathematical modeling of the primary cilium and how it couples to the intracellular signaling pathways. This award is co-funded with the Cellular Dynamics and Function program in Division of Molecular and Cellular Biosciences, and the Life Science Venture Fund in DMS.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.