Understanding the skeleton in Down Syndrome

总结/摘要 这个新的R 01应用程序题为“了解唐氏综合症的骨量”，重点是确定 我们在唐氏综合症患者和小鼠中发现的低骨转换的细胞机制 (DS)，并在不同的DS小鼠模型中表征骨折愈合反应，以深入了解 在骨折倾向增加的DS人群中更好地靶向骨折愈合。这项建议会 确定钙调神经磷酸酶1（RCAN 1）的作用，该作用影响NF-κB活性， 破骨细胞和成骨细胞/骨细胞中的Wnt信号传导与骨矿物质密度（BMD）固有的低水平有关， DS.拟议的实验还将确定停止目前临床骨合成代谢的影响。 在DS背景下的干预以及定义DS骨折愈合。目标1将阐明 RCAN 1通过其控制破骨细胞和成骨细胞的分化和功能。目标2将提供 在低骨增量和DS背景下骨折愈合和修复的第一个直接证据。目标3将 确定当前药物合成代谢疗法（抗sclerostin抗体）停止的影响 和间歇性PTH）对三种临床前DS小鼠模型中骨量增加的影响。成功 这项研究的完成将使我们对DS骨表型的理解发生范式转变， 高质量研究的景观，将提供有助于低的机制澄清 更重要的是，为骨折治疗的新方向提供了基础 和严重的骨质疏松症

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.