Mechanistic investigation into Frizzled-2 signaling for treatment of Osteogenesis Imperfecta

摘要 成骨不全(OI)是一组遗传和表型不同的结缔组织 骨质疏松症导致骨量减少、骨骼畸形和骨折的疾病。OI的患病率估计为 每15,000名新生儿中就有1名。多个过程的中断，如胶原合成、胶原翻译后 修饰、信号缺陷和细胞内转运导致OI。医学治疗的主要焦点是 一直致力于通过内科和外科治疗增加骨量和降低骨折风险。的中流砥柱 这一人群的治疗方法是双磷酸盐，它通过抑制骨转换来减少骨丢失。 然而，这些药物只能延缓骨丢失，而不能完全预防它。我们已经证明了调制 WNT/Frizzled2信号通路可增加野生型小鼠的骨量。我在这个项目中的目标是 测试Wnt/Frizzled2信号通路是否可用于治疗显性和非骨质疏松症的骨骼特征 隐性OI减少Wnt1sw/Sw小鼠模型的小脑功能障碍并研究其调节机制 在Wnt/Frizzled2信号通路中增加骨量。我们的初步研究表明，这种调制 在OI的显性(Col1a2tm1.1Mcbr)和隐性(Crap-/-)模型中增加骨量。在其他预赛中 研究发现，我发现调节Wnt/Frizzled2通路会增加mTORC1下游的激活 信号通路。中心假说是Wnt/Frizzled2信号通路的调制 通过激活mTORC1信号通路的下游靶点来增加骨量。我们计划 通过以下方式验证我们的假设：在两个OI小鼠模型中，用 一个调制的Wnt/Frizzled2信号分子，评估骨外表型的变化 建立Wnt1sw/Sw小鼠模型，研究Wnt/Frizzled2信号在体内和体内mTORC1通路中的作用 体外对骨量和细胞增殖及功能的影响。通过评估这些目标，我们将 阐明Wnt/Frizzled2信号在骨形成中的作用，并深入了解下游的激活 MTORC1信号通路的改变改变了骨形成。

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.