Understanding the skeleton in Down Syndrome

摘要/摘要 这个名为“了解唐氏综合症患者的骨量”的新R01应用程序的重点是确定 唐氏综合征患者和小鼠骨转换率低的细胞机制 (DS)，以及不同DS小鼠模型的骨折愈合反应的特征，以深入了解 在骨折倾向增加的DS人群中更好地达到骨折愈合的目标。这项提议将 确定钙调神经磷酸酶1(RCAN1)调节因子对核因子-κB活性的影响 破骨细胞和Wnt信号在成骨细胞/骨细胞中对先天性低骨密度的作用 DS.拟议的实验还将确定停止目前的临床骨合成代谢的影响 对DS环境的干预以及对DS骨折愈合的定义。目标1将阐明这些途径 RCAN1通过其调控破骨细胞和成骨细胞的分化和功能。AIM 2将提供 在低骨累积量和DS的情况下骨折愈合和修复的第一个直接证据。目标3将 确定停止当前药物合成代谢疗法(抗硬化素抗体)的效果 和间歇性甲状旁腺激素)对三种临床前DS模型小鼠的骨量增加的影响。成功者 这项研究的完成将导致我们对DS骨表型的理解的范式转变和一个新的 高质量研究的前景，将澄清导致低血压的机制 DS的骨量，更重要的是为骨折的治疗提供新的方向 以及严重的骨质疏松症，影响着这一人群。

SUMMARY/ABSTRACT This new R01 application entitled “Understanding bone mass in Down Syndrome” is focused on determining the cellular mechanism for the low bone turnover we have identified in people and mice with Down Syndrome (DS), and on characterizing fracture healing responses in different DS mouse models to gain insight into how to better target fracture healing in the DS population with increased propensity to fracture. This proposal will determine the contribution of Regulator of calcineurin 1 (RCAN1) that impacts both NF-κB activity in osteoclasts and Wnt signaling in osteoblasts/osteocytes to the inherently low bone mineral density (BMD) in DS. The proposed experiments will also determine the impact of cessation of the current clinical bone anabolic interventions in the setting of DS as well as define DS fracture healing. Aim 1 will elucidate the pathways through which RCAN1 controls osteoclast and osteoblast differentiation and function. Aim 2 will provide the first direct evidence of fracture healing and repair in the context of low bone accrual and DS. Aim 3 will determine the effects of discontinuation of current pharmaceutical anabolic therapies (anti-sclerostin antibody and intermittent PTH) on bone mass accrual in three preclinical mouse models of DS. The successful completion of this study will lead to a paradigm shift in our understanding of the DS bone phenotype and a new landscape of high-quality research that will provide clarification of the mechanisms that contribute to the low bone mass in DS and more importantly, provide the basis for new directions for the treatment of the fractures and profound osteopenia that affects this population.