Christopher R. Jacobs
Columbia University
Tuesday, November 11, 2014, 10:30 am, 801 22nd Street NW, Phillips Hall 736
Abstract: Cellular mechanosensation is critical in diseases responsible for enormous human suffering including atherosclerosis, osteoarthritis, cancer, and osteoporosis. Nonetheless, very little is understood about the molecular mechanisms of mechanotransduction outside of a small number of specialized sensory cells. Primary cilia are solitary linear cellular extensions that extend from the surface of virtually all cells. For decades, the biologic function of these enigmatic structures was elusive, however, recent evidence suggests an emerging picture in which the primary cilium functions as a complex nexus where both physical and chemical extracellular signals are sensed and responses coordinated. In our laboratory we have shown that primary cilia act as mechanical sensors in bone and that conditional deletion of primary cilia lead to mechanosensing defects. Additionally mice that receive bone marrow transplants from donors lacking primary cilia have a blunted response to loading, suggesting that they are important in stem cell proliferation, differentiation, migration, and/or engraftment. Recently, we developed a novel combined experimental/modeling approach to determine the mechanical properties of primary cilia. We found a wide variety of previously unreported deformation modes including smooth bending and rigid-body rotations. This suggests that the mechanics of both the cilium shaft and basal anchorage are important to understanding deflection patterns. Interestingly, both the cilium itself and its anchorage to the microtubule cytoskeleton alter their structure in response to physical loading, suggesting structural adaptation or “remodeling”. We have also developed novel molecular biology tools to elucidate the details of mechanically activated ciliary signaling pathways. For example, we have created a cilia-directed biosensor that has allowed us to distinguish intraciliary from intracellular calcium signaling. We have also developed a method for distinguishing the roles of the cytoplasmic and ciliary pools of proteins that are found in both compartments. In summary, primary cilia are non-linear, richly varied, mechanical structures (biomechanics) as well as structurally adaptive (mechanobiology). Simultaneously they are a biochemical microdomain where signaling events are catalyzed, enhanced, and integrated. It seems likely that we have only just begun to appreciate the wide range of cellular functions and dysfunction in which primary cilia play a crucial role.
Biographical Sketch: Dr. Jacobs received in PhD in Mechanical Engineering in 1994 form Stanford University. His first faculty position was in Orthopaedic Surgery at Penn State. In 2001 he returned to Stanford as an Associate Professor of Mechanical Engineering. In 2008 he joined the Biomedical Engineering Department at Columbia University, where he is pursuing a vision of the future of biomechanics and mechanobiology at the cell and molecular levels. The goal of his lab, the Cell and Molecular Biomechanics Lab, is to investigate cellular mechanosensing, particularly in the skeleton, with tightly coupled integration of advanced theoretical mechanics and modern molecular biology. He has made discoveries in terms of the mechanical signals that bone cells sense and respond to and how these responses are communicated and integrated between cells. This has directly brought them to their current research question, understanding novel mechanisms for how these signals are transduced at a cellular level. Most recently his lab has identified primary cilia, enigmatic structure found in virtually all cell type, as a mechanosensor both in vitro and in vivo. They are currently investigating the mechanisms of intracellular signaling initiated by primary cilia with novel molecular biology strategies and relating those events to primary cilia biomechanical behavior and properties. They have unique evidence that cells may adapt their mechanosensitivity by modulating cilium mechanics. To date he has been awarded over $7.5 million from federal and state agencies including for individual investigator projects, as well as $9.5 million in center grants. He has published over 100 peer-reviewed papers, 2 books, and 9 book chapters. He is the senior author of the innovative textbook “Introduction to Cell Mechanics and Mechanobiology”, which has been adopted in 35 courses with an enrollment of over 850 students worldwide since it publication in 2013. He has received research awards from the American and European Societies of Biomechanics, and the Yasuda Award from the Society for Physical Regulation in Medicine and Biology. He is the 2014 recipient of the Van C. Mow medal for bioengineering from the American Society of Mechanical Engineers.