Project Summary Candidate: Rachel E. Miller, PhD is an Assistant Professor of Medicine (Division of Rheumatology) at Rush University Medical Center, Chicago, IL. Dr. Miller is seeking a Mentored Research Scientist Development Award in order to obtain additional training in neurobiology and physiology laboratory techniques necessary for her to develop an independent research program focused on better understanding the mechanophysiology of OA pain. Specifically, Dr. Miller will receive training in electrophysiology and calcium signaling techniques, as well as training in applying custom-built mechanical loading. Therefore, this career development award will complement her graduate and postdoctoral training by providing her with the additional expertise necessary for forging an independent research program bridging: musculoskeletal biology, biomechanics, neuroscience, and physiology. This research is expected to provide novel insights into the signaling pathways responsible for the pain associated with aberrant mechanical loading, which could ultimately be translated into improved therapeutics for OA. This award would enable her to devote 75% FTE to the training and science proposed. In addition to scientific training, she will benefit from attendance and presentation in seminars and scientific meetings, training in the responsible conduct of research, and training in manuscript writing and grantsmanship. Environment: Dr. Miller recently accepted an Assistant Professor position at Rush University in the Department of Internal Medicine, Division of Rheumatology. The Rush Arthritis and Orthopedics Institute, comprising the Departments of Orthopedics, Anatomy & Cell Biology, Rheumatology, and Biochemistry, provides an academic translational research community that combines excellent basic and clinical research for the study of osteoarthritis. In addition, the close proximity to Northwestern Medical Campus allows for close collaboration with experts in neuroscience and physiology. Finally, faculty members in the Department of Molecular Biophysics and Physiology at Rush have active research programs in a variety of areas including the functions of cell membranes and ion channels, and whose experience will benefit Dr. Miller's proposed research. Dr. Miller has the full support of the Division of Rheumatology and the Division guarantees that Dr. Miller will have more than 75% time protected for K01-related research and training throughout the term of this award, and, to pursue the objectives of this application, she will have minimal administrative, committee, and lecturing obligations. She will have access to all of the faculty expertise, mentorship, laboratory space and equipment, and career development resources necessary to help her to reach her goal of becoming an independent researcher. Research: This proposal focuses on improving the understanding of why weight-bearing activity causes pain in osteoarthritis. Osteoarthritis (OA) of the knee is a painful disease, characterized by progressive damage and remodeling of all joint tissues. Abnormal mechanical forces play an important role in driving the development of knee OA. During weight-bearing activities, including walking and climbing stairs, the damaged area is subjected to increased focal stresses, leading to more damage. The same weight-bearing activities are associated with pain in OA. Chronic stimulation of sensory nerves, such as in OA, may lead to sensitization and chronic pain. Therefore, treating early OA pain associated with mechanical input may be important for preventing chronic pain. Our hypothesis is that aberrant mechanical forces within the knee joint, known to promote joint damage, also promote pain. We propose that activity-associated pain may occur through direct mechanical stimulation of peripheral nerve termini or through secondary production of pro-algesic molecules by other joint tissues (including cartilage, which is aneural). This hypothesis will be addressed through the following aims: Aim 1: Evaluate responses of peripheral sensory nerve termini within joint tissues to mechanical stimuli after destabilization of the medial meniscus (DMM) in the mouse; Aim 2: Determine which mechanical stimuli can induce pro-algesic molecule production by chondrocytes; Aim 3: Identify classes of ion channels expressed by chondrocytes and evaluate mechanical function.