Investigating injury response and bone regeneration in Down syndrome mouse models

项目摘要/摘要 唐氏综合征(DS)是由人类21号染色体三体(Hsa21)引起的一种常见出生缺陷。DS导联 一系列影响身体大多数系统的临床异常，包括伤口愈合延迟，以及 长骨和脊椎骨折的风险增加。此前，该实验室已经证明DS患者 骨转换率低导致骨密度降低，成人骨高峰出现延迟 质量，也证实了DS模型小鼠的低骨量表型。此外，它一直是 最近报道，在DS人真皮成纤维细胞中，COX2/PGE2的表达受到损害，这可能 在DS人群中导致伤口愈合延迟和感染风险增加。前列腺素E_2及其相关基因 受体是炎症、伤口愈合、骨形成和骨愈合的主要介质。更多 具体地说，PGE2受体亚单位2(EP2，Ptger2)和EP4已被证明调节骨形成， 在骨折愈合中起关键作用，而EP3和EP4有助于巨噬细胞的募集， 伤口愈合中的免疫反应和淋巴管生成。然而，尚不清楚的是PGE2是如何 信号转导有助于骨修复，以及DS中低骨积累是否会影响骨再生。这个 这项建议的首要目标是确定DS小鼠模型的骨愈合特征，并确定 在再生过程中的不同阶段进行药物处理能够促进再生 DS.这个项目将检验这一假说，即DS患者的骨骼愈合显著受损，而且减少了 骨周转导致骨再生减弱。本研究将利用DS小鼠模型Dp16和 Ts65Dn，这表明DS的低骨量表型与观察到的低骨量一致 患者，研究终节指骨切断后的新骨再生(P3)。P3截肢 是一种哺乳动物损伤的模型，它忠实地触发了一系列定义明确的再生事件， 炎症伴随着骨吸收、伤口闭合和新生骨形成，使得 整个伤害反应的特征。目标1中的实验将寻求表征P3再生在 将DS小鼠模型与WT小鼠模型进行比较，以验证骨再生在 DS小鼠模型。目标2将研究再生的早期或裂解阶段，并确定 使用PGE2受体(EP3和EP4)激动剂治疗可引起免疫和伤口愈合反应，即 足以增强DS的再生能力。拟议的新骨再生研究将有助于结束 关于DS如何影响骨愈合和修复的知识差距，并提供对患者如何的洞察 可以修改CARE以充分治疗高危DS人群中的骨损伤。

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.