ABSTRACT Chronic degeneration of the rotator cuff leads to tendon tears and poor healing after surgical repair, with failure rates after repair ranging from 20-94%, depending on the patient population. Repair-site rupture is primarily due to poor tendon-to-bone healing: high levels of inflammation lead to fibrovascular scar rather than aligned collagen, and a fibrocartilaginous transition between tendon and bone is not regenerated. Our overall objective is to determine the drivers of degeneration using mouse models and then to test treatment strategies related to these mechanisms in a chronic rat rotator cuff repair model. We have identified two critical features of degeneration and poor healing: inflammation and a lack of fibrocartilage formation. Specifically, there is dramatic upregulation of the NFκB inflammatory pathway during tendon healing and a requirement for hedgehog (Hh) signaling in the formation of fibrocartilage between tendon and bone. Therefore, the current proposal focuses on these two pathways for preventing degeneration and enhancing healing. Specific Aim 1 seeks to determine the role of inflammation, and the NFκB pathway in particular, in rotator cuff degeneration and healing. Inflammation will be modulated genetically in mouse models via the activation and deletion of IKKB, a factor required for NFκB signaling. IKKB will be modulated in tenocytes and muscle cells using inducible Cre models. To test the therapeutic potential of targeting harmful inflammatory cytokines, an IKKB inhibitor will be delivered to rats with repaired chronically degenerated rotator cuffs. Specific Aim 2 will determine role of Hh signaling for fibrocartilage loss during cuff degeneration and fibrocartilage formation during healing. We will first determine the role of Hh signaling for mineral loss at the healing cuff by deleting signaling genetically (via tenocyte- or osteoblast-specific inducible Cre models) or increasing signaling with a Hh agonist. A rat animal model of chronic rotator cuff degeneration followed by repair will then be used to test the efficacy of a Hh agonist for enhanced tendon-to-bone healing.