Abstract Osteogenesis imperfecta (OI) is a group of genetically and phenotypically heterogeneous connective tissue disorders that results in low bone mass, bone deformity, and bone fractures. OI has an estimated prevalence of 1 in 15,000 births. Disruptions in multiple processes such as collagen synthesis, collagen posttranslational modification, signaling defects and intracellular trafficking lead to OI. The primary focus of medical therapy has been to increase bone mass and reduce fracture risk through medical and surgical treatment. The mainstay of treatment in this population is bisphosphonates, which reduces bone loss by suppressing bone turnover. However, these drugs can only delay bone loss without fully preventing it. We've shown that modulation of the Wnt/Frizzled2 signaling pathway can in increase bone mass in wild type mice. My objective in this project is to test whether the Wnt/Frizzled2 signaling pathway can be used to treat both skeletal features of a dominant and recessive form OI, reduce cerebellar dysfunction in the Wnt1sw/sw mouse model and investigate how modulation in the Wnt/Frizzled2 signaling pathway increases bone mass. Our preliminary studies indicate this modulate increases bone mass in a dominant (Col1a2tm1.1Mcbr) and recessive model of OI (Crtap-/-). In other preliminary studies, I found that modulating the Wnt/Frizzled2 pathway increases downstream activation of the mTORC1 signaling pathway. The central hypothesis is that modulation of the Wnt/Frizzled2 signaling pathway increases bone mass through activation of downstream targets of the mTORC1 signaling pathway. We plan to test our hypothesis in the following ways: characterize the skeletal in two OI mouse models after treatment with a modulated Wnt/Frizzled2 signaling molecule, assess the changes in the extraskeletal phenotype in the Wnt1sw/sw mouse model and investigate the role of Wnt/Frizzled2 signaling in mTORC1 pathway in vivo and in vitro on bone mass and cellular proliferation and function, respectively. By assessing these aims, we will elucidate the role of Wnt/Frizzled2 signaling in bone formation and gain insight on how downstream activation of the mTORC1 signaling pathway alters bone formation.