Project Summary/Abstract Down Syndrome (DS) is a common birth defect caused by trisomy of human chromosome 21 (Hsa21). DS leads to a vast array of clinical abnormalities affecting most systems of the body, including delayed wound healing, and an increased risk of long bone and vertebral fractures. Previously, this laboratory has shown that DS patients have low bone turnover leading to decreased bone mineral density and delayed accrual of peak adult bone mass, and also confirmed the low bone mass phenotype in mouse models of DS. Additionally, it has been recently reported that COX2/PGE2 expression is impaired in DS human dermal fibroblasts, which could contribute to the delayed wound healing and increased risk of infections in the DS population. PGE2 and its receptors are major mediators of inflammation, wound healing, bone formation and bone healing. More specifically, the PGE2 receptor subunit 2 (EP2, Ptger2) and EP4, have been shown to regulate bone formation, and play a crucial role in fracture healing, whereas EP3 and EP4 contribute to macrophage recruitment, the immune response, and lymphangiogenesis in wound healing. However, what is not known is how PGE2 signaling contributes to bone repair and whether low bone accrual in DS impacts bone regeneration. The overarching objective of this proposal is to characterize bone healing in DS mouse models and determine if pharmaceutical treatment at different stages during the regenerative process is able to enhance regeneration in DS. This project will test the hypothesis that bone healing is significantly impaired in DS, and that decreased bone turnover leads to attenuated bone regeneration. This study will utilize the DS mouse models, Dp16 and Ts65Dn, that demonstrate the low bone mass phenotype consistent with the low bone mass observed in DS patients, to investigate de novo bone regeneration after amputation of the terminal phalanx (P3). P3 amputation is a model of mammalian injury that faithfully triggers a well-defined regenerative sequence of events that initiates with inflammation followed by bone resorption, wound closure, and de novo bone formation, allowing the characterization of the entire injury response. Experiments in Aim 1 will seek to characterize P3 regeneration in the DS mouse models compared to WT littermates to test the hypothesis that bone regeneration is impaired in DS mouse models. Aim 2 will investigate the early, or lytic, phase of regeneration and determine whether treatment with a PGE2 receptor (EP3 and EP4) agonist elicits an immune and wound healing response that is sufficient to enhance regeneration in DS. The proposed studies of de novo bone regeneration will help to close the gap in knowledge regarding how DS impacts bone healing and repair, and provide insight into how patient care can be modified to adequately treat bone injuries in the at-risk DS population.