Biomarking the Sclerostin Antibody Effects on Osseointegration in an Osteogenesis Imperfecta Model

项目摘要/摘要 成骨不全是一种遗传性发育不良，以脆性骨质疏松症、骨折增多和低位发育为特征。 骨密度。目前的OI管理主要依赖于长期的抗吸收治疗，以防止 骨折，但可能会干扰正常的颌骨愈合。硬化素抗体是治疗OI的新策略 (SclAb)，可诱导强烈的合成代谢反应以增加骨密度。虽然SclAb增加了骨骼 形成并显著改善长骨生物力学性能，长期连续给药 通过增加Wnt拮抗剂的表达，迅速降低骨形成反应。循环SclAb治疗 在长骨研究的基础上，无抗体时期恢复了骨形成反应，因此知之甚少 这一策略如何影响颌骨和种植体骨整合(骨愈合)。种植体稳定性成功 (一期愈合)和骨整合(长期愈合)取决于良好的骨密度。因此，要预测 种植体植入前后颌骨骨密度变化的临床意义 合成代谢作用。使用microRNAs(MiRNAs)作为OI的生物标志物是很有吸引力的。发现在以下方面扮演关键角色 骨内稳态相关途径的调控，骨重建相关的miRNAs可能取代 目前的非特异性骨密度诊断工具，导致了OI的个性化药物治疗方法 治疗管理。本研究有两个目的。目的1：阐明SclAb周期治疗的最佳方案 诱导和维持颌骨形成反应及其对骨整合的影响。目标2：实现 确定检测或预测SclAb治疗结果的骨重建相关miRNA面板以指导 植入物的放置决定。这项提案的结果将提供SclAb治疗时间表 诱导和维持最佳的骨合成代谢效果，而不影响愈合和miRNA面板 合成代谢和吸收时相可用于关联SclAb对牙科和牙周病患者骨代谢的影响 低骨量患者的骨科治疗决策和长期疾病监测。 应聘者坚定地致力于开发有效的、临床适用的口腔颌面部骨骼。 改善低骨量障碍患者生活质量的再生策略。她的导师， 咨询委员会成员和密歇根大学口腔颌面外科 牙医学院强烈支持候选人以及她的职业和研究目标。她目前持有 助理教授的职位，博士研究项目有20%的保护时间。建议数 实验和教学工作将使她拥有一套独特的跨学科技能，使她能够 作为一名外科医生-科学家过渡到独立，专注于翻译性颅面再生 医学。

Project Summary/abstract Osteogenesis Imperfecta is a genetic dysplasia characterized by brittle bone, increased bone fracture and low bone density. Current OI management relies mainly upon long-term anti-resorptive treatments that prevent fractures, yet may interfere with normal jaw bone healing. A novel strategy for OI treatment is Sclerostin Antibody (SclAb), which induces a strong anabolic response to increase bone density. Although SclAb increases bone formation and significantly improves the biomechanical long bone properties, long-term continuous dosing rapidly decreases bone-formation response by increasing Wnt antagonist expression. Cycling SclAb treatments with antibody-free periods restores bone-formation response based on long bone research, so little is known how this strategy affects jaw bone and implant osseointegration (bone healing). Successful implant stability (primary healing) and osseointegration (long-term healing) depends on good bone density. Therefore, to predict jaw bone density in OI before and after implant placement, there is a clinical need to biomark SclAb-induced anabolic effects. The use of MicroRNAs (miRNAs) as biomarkers for OI is attractive. Found to play key roles in the regulation of bone homeostasis-related pathways, bone-remodeling-related miRNAs may possibly replace the current nonspecific bone density diagnosis tools, resulting in a personalized medicine approach for OI treatment management. There are 2 aims in this study. Aim 1: Elucidate the optimal SclAb-cycle therapy regimen that induces and sustains the jawbone formation response and its effect on osseointegration. Aim 2: To determine the bone-remodeling-related miRNA panels that detect or predict SclAb treatment outcome to guide implant placement decisions. The results of this proposal will provide both the SclAb therapy schedule that induces and sustains the optimal bone anabolic effects without affecting the healing and miRNA panels of anabolic and resorptive phase that can be used to correlate the SclAb effects on bone metabolism for dental and orthopedic treatment decisions and long-term disease monitoring of low bone mass patients. The candidate is firmly committed to a career in developing effective, clinically applicable orofacial bone regeneration strategies to improve the quality of life among low bone mass disorder patients. Her Mentor, Advisory Committee Members and the Oral and Maxillofacial Surgery Department at the University of Michigan School of Dentistry strongly support the candidate and her career and research goals. She currently holds a position as an Assistant Professor with 20% protected time for her PhD research project. The proposed experiments and didactic work will position her with a unique set of cross-disciplinary skills, enabling her transition to independence as a surgeon-scientist with a focus in Translational Craniofacial Regenerative Medicine.