The research objective of this award is to investigate the fundamental mechanisms by which adult stem cells translate hydrostatic pressure into a biological signal that produces cartilage matrix. Hydrostatic pressure is the primary manner that loads are carried in cartilage and has been shown to enhance the matrix production of cartilaginous cells. However, surprisingly little is currently known about how hydrostatic pressure induces these cellular changes. Studies conducted under this award will investigate the roles of calcium signaling, cytoskeletal components, and integrin binding in translating the mechanical signal to a biological one. In particular, how these three elements interact in the translation of hydrostatic pressure will be determined. The research will use pharmacological inhibitors, shRNA and live cell imaging to investigate the mechanobiology of this dominant loading modality.
If successful, these studies will establish a framework for understanding how calcium signaling, the cytoskeleton and integrin binding cooperate to induce adult stem cells to produce cartilage matrix as a response to hydrostatic pressure. Advancing our understanding of the mechanical regulation of cartilage matrix production may lead to the development of improved therapeutic interventions and tissue engineering strategies to treat the debilitating cartilage defects that eventually progress to arthritis. In addition to its potential impact on cartilage tissue regeneration, the work will be applicable to related tissues such as the meniscus and the intervertebral disc, where the majority of loading in vivo is also supported by hydrostatic pressure. Finally, the proposal includes an outreach plan in conjunction with a local high school to introduce students to cell-based therapies, bioengineering and laboratory research.
