Temporal balance between Notch and Wnt signaling during fracture healing

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 DESCRIPTION (provided by applicant): The field of stem cell biology is advancing at an incredible speed, with new techniques emerging on a regular basis allowing for deeper investigations into the mechanisms underlying adult stem cell biology and tissue regeneration. Wnt signaling and Notch signaling have been identified as two key pathways that regulate adult stem cell proliferation and differentiation. Past research has focused on the role of Wnt signaling during bone regeneration, in particular on its role as a stem cell activator and pro-osteogenic growth factor. The Notch signaling pathway, however, has not received much attention, even though there is good evidence in embryonic development and adult tissue regeneration (i.e. muscle) that the Notch signaling pathway plays a central role in progenitor cell proliferation. In this proposal, we will focus on the Notch and Wnt signaling pathway, in particular how the two pathways orchestrate early stem cell proliferation and differentiation. (1) We will first characterize the Notch and Wnt responsiveness of osteoprogenitor cells within the injury site and map the spatial and temporal expression profile of members of both pathways. (2) We will then inhibit Notch signaling during the early proliferative phase, which will identify the degree t which Notch signaling regulates proliferation and potentially influences subsequent differentiation. (3) In the last aim, we will independently activate Notch and Wnt signaling in viv to define the potential coordinate activity between the two pathways during adult bone stem cells activation. While much effort has been exerted into identifying the effect of a singular growth hormone on bone regeneration, our research seeks to characterize a well-orchestrated interplay between two well-known pathways. This proposal may expose potential therapeutic targets, which may result in the future development of biomimetic treatment algorithms with the goal of enhancing the body's own regenerative capacity. My career goal is to conduct clinically relevant basic research as an orthopaedic clinician scientist. This career development plan and research proposal will allow me to focus my efforts on acquiring the desired skills that are necessary to become a successful clinician scientist. Receiving mentorship from my two highly accomplished primary mentors in addition to the five members of my advisory committee will guarantee my gradual growth into a competitive researcher in the field of bone biology. This expected academic growth in addition to the acquired new skills sets will place me in a prime position to compete for independent R01 funding.