CAREER: Integrin-Mediated Mechanotransduction of Articular Chondrocytes

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This Faculty Early Career Development (CAREER) award will focus on elucidating the molecular mechanisms associated with the development of osteoarthritis. Osteoarthritis is the type of arthritis that occurs with age or injury. Mechanical force is a key contributing factor to the development of osteoarthritis. However, substantial gaps remain in our understanding of the mechanisms by which mechanical forces lead to biological behaviors can lead to osteoarthritis. This work will focus specifically on cells in cartilage, which are called chondrocytes. This project will elucidate molecular mechanisms by which articular chondrocytes determine cartilage tissue health. Specifically, this work will examine the relation of mechanical inputs to biological outputs mediated through the transmission of forces across specific mechanoreceptors that connect the fibrous environment outside the cell with the structural components inside the cell. This research will have eventual application to future biomechanical or pharmaceutical interventions to prevent or reverse osteoarthritis. The research from this project will also be integrated into an educational and outreach program based on graduate and undergraduate curriculum development, promotion of graduate and undergraduate research opportunities, and K-12 and regional underrepresented minority outreach through the development of educational story books and hands-on summer camp activities.The specific goal of the research is to determine the integrin-mediated mechanotransduction mechanisms by which articular chondrocytes regulate cartilage homeostasis, and thus to advance understanding of the pathogenesis of osteoarthritis. The research objectives include: (1) establishing a baseline catabolic threshold for tensile force applied to chondrocyte integrins, (2) determining the degree to which actin dynamics drives chondrocyte preference for dynamic force, and (3) establishing surface glycoproteins as modulators of chondrocyte integrin tension dynamics via application of prestress. The overarching focus will be on leveraging mechanical concepts developed initially for civil and mechanical engineering to investigate mechanisms of outside-in mechanotransduction, inside-out mechanotransduction, and molecular tensegrity to obtain a better understanding of integrin-mediated mechanotransduction in articular chondrocytes. Education and outreach components will integrate research results into graduate and undergraduate coursework and research opportunities, storybooks introducing Native American elementary students to principles of cellular mechanobiology, and hands-on summer camp activities for middle and high school students. This project will advance the knowledge base in cellular vibrational analysis, molecular tensegrity, and cellular mechanobiology and establish his long-term career at the intersection of nanoscience, nanoengineering, and biomedical engineering.This project is jointly funded by the Biomechanics and Mechanobiology Program and the Established Program to Stimulate Competitive Research (EPSCoR).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.