Investigating injury response and bone regeneration in Down syndrome mouse models

研究唐氏综合症小鼠模型的损伤反应和骨再生

• 批准号: 10697127
• 负责人: Kirby M. Sherman
• 金额: $ 3.86万
• 依托单位: TEXAS A&M UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10697127
• 关键词: Adult; Affect; Agonist; Amputation; Attenuated; Bone Density; Bone Injury; Bone Regeneration; Bone Resorption; Chromosome 21; Clinical; Congenital Abnormality; Data; Dermal; Digit structure; Dinoprostone; Distal; Down Syndrome; EP4 receptor; Event; Exhibits; Fibroblasts; Fracture; Frequencies; Genetic Diseases; Harvest; Human; Human Chromosomes; Immune; Immune response; Immunohistochemistry; Impaired wound healing; Impairment; Inflammation; Inflammation Mediators; Inflammatory; Injury; Knowledge; Laboratories; Length; Live Birth; Lymphangiogenesis; Lytic; Lytic Phase; Macrophage; Modeling; Monitor; Mus; Natural regeneration; Osteogenesis; PTGS2 gene; Patient Care; Patients; Phalanx; Pharmacologic Substance; Phase; Phenotype; Play; Population; Process; Prostaglandin E Receptor; Prostaglandins; Regenerative response; Reporting; Research; Risk; Role; Signal Transduction; Spinal Fractures; Testing; Time; Tissues; Trisomy; WFDC2 gene; X-Ray Computed Tomography; body system; bone; bone fracture repair; bone healing; bone health; bone mass; bone repair; bone turnover; digit regeneration; experience; experimental study; fracture risk; healing; histological stains; improved; in vivo; infection risk; injury and repair; insight; long bone; male; microCT; mouse Ts65Dn; mouse model; novel; receptor; recruit; regenerative; repaired; response; response to injury; tissue injury; tissue repair; wound; wound closure; wound healing

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.

项目概要/摘要 唐氏综合症（DS）是一种常见的出生缺陷，由人类21号染色体（Hsa21）三体性引起。 DS 引线 影响身体大多数系统的大量临床异常，包括伤口愈合延迟，以及 长骨和椎骨骨折的风险增加。此前，该实验室已证明 DS 患者 骨转换率低，导致骨矿物质密度降低并延迟成年骨峰值的累积 质量，并证实了 DS 小鼠模型中的低骨量表型。此外，它还被 最近报道 DS 人真皮成纤维细胞中 COX2/PGE2 表达受损，这可能 导致 DS 人群伤口愈合延迟和感染风险增加。 PGE2及其 受体是炎症、伤口愈合、骨形成和骨愈合的主要介质。更多的 具体来说，PGE2 受体亚基 2（EP2、Ptger2）和 EP4 已被证明可以调节骨形成， 在骨折愈合中发挥着至关重要的作用，而 EP3 和 EP4 则有助于巨噬细胞的募集， 免疫反应和伤口愈合中的淋巴管生成。然而，目前尚不清楚的是 PGE2 是如何 信号传导有助于骨修复，以及 DS 中骨生成量低是否会影响骨再生。这 该提案的首要目标是描述 DS 小鼠模型中骨愈合的特征，并确定是否 再生过程中不同阶段的药物治疗能够增强再生能力 DS。该项目将检验 DS 患者骨愈合明显受损的假设，并且骨愈合下降 骨转换导致骨再生减弱。本研究将利用 DS 小鼠模型、Dp16 和 Ts65Dn，表明低骨量表型与 DS 中观察到的低骨量一致 患者，研究末节指骨截肢后的从头骨再生（P3）。 P3截肢 是一种哺乳动物损伤模型，它忠实地触发了明确的再生事件序列，从而启动 炎症后骨吸收、伤口闭合和从头骨形成，使 整个损伤反应的特征。目标 1 中的实验将寻求表征 P3 再生的特征 将 DS 小鼠模型与 WT 同窝小鼠进行比较，以检验骨再生受损的假设 DS 鼠标型号。目标 2 将研究再生的早期或裂解阶段，并确定是否 使用 PGE2 受体（EP3 和 EP4）激动剂治疗可引发免疫和伤口愈合反应， 足以增强 DS 的再生。拟议的从头骨再生研究将有助于关闭 关于 DS 如何影响骨愈合和修复的知识差距，并深入了解患者如何 可以对护理进行修改，以充分治疗 DS 高危人群的骨损伤。

项目成果

Microcomputed tomography staging of bone histolysis in the regenerating mouse digit.

再生小鼠手指骨组织溶解的微计算机断层扫描分期。

• 发表时间: 2023-01
• 作者: Ketcham, Paulina D;Imholt, Felisha;Yan, Mingquan;Smith, Hannah M;Asrar, Shabistan;Yu, Ling;Dolan, Connor P;Qureshi, Osama;Lin, Yu;Xia, Ian;Hall, Patrick C;Falck, Alyssa R;Sherman, Kirby M;Gaddy, Dana;Suva, Larry J;Muneoka, Ken;Brunaue
• 通讯作者: Brunaue