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.

项目摘要/摘要 唐氏综合症（DS）是由人类染色体21（HSA21）引起的常见先天缺陷。 DS领导 有一系列影响人体大多数系统的临床异常，包括伤口延迟的愈合和 长骨和椎骨骨折的风险增加。以前，该实验室表明DS患者 骨转换较低，导致骨矿物质密度降低并延迟成年骨骼 质量，还证实了DS小鼠模型中的低骨质量表型。另外，已经 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人群中伤口延迟的愈合和感染风险增加。 PGE2及其 受体是炎症，伤口愈合，骨形成和骨愈合的主要介体。更多的 具体而言，已证明PGE2受体亚基2（EP2，PTGER2）和EP4可以调节骨形成， 并在骨折愈合中起着至关重要的作用，而EP3和EP4有助于巨噬细胞募集， 免疫反应和伤口愈合中的淋巴管发生。但是，尚不清楚的是PGE2如何 信号传导有助于骨骼修复，而DS中的低骨值是否会影响骨骼再生。这 该建议的总体目标是表征DS小鼠模型中的骨骼愈合，并确定是否是否 再生过程中不同阶段的药物处理能够增强再生 DS。该项目将检验以下假设：DS中的骨骼愈合受到了显着损害，该假设减少了 骨转换导致骨骼再生。这项研究将利用DS鼠标模型DP16和 TS65DN，证明了与DS中观察到的低骨质量一致的低骨质量表型 患者，研究末端卵泡截肢后的从头再生（P3）。 P3截肢 是一种哺乳动物损伤的模型 炎症，然后进行骨吸收，伤口闭合和从头形成，从而使 整个伤害反应的表征。 AIM 1中的实验将寻求表征P3的再生 DS小鼠模型与WT同窝仔相比，以测试骨再生受损的假设 DS鼠标模型。 AIM 2将研究再生的早期或裂解阶段，并确定是否是否 用PGE2受体（EP3和EP4）激动剂的治疗引起免疫和伤口愈合反应 足以增强DS的再生。提出的关于从头骨再生的研究将有助于关闭 关于DS如何影响骨骼愈合和修复的知识差距，并洞悉如何患者 可以修改护理以充分治疗高危DS人群中的骨骼损伤。