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

生物标记硬化素抗体对成骨不全模型中骨整合的影响

• 批准号: 10440532
• 负责人: Hsiao Hsin Sung Hsieh
• 金额: $ 15.01万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10440532
• 关键词: Advisory Committees; Affect; Algorithms; Antibodies; Antibody Therapy; Biological Markers; Biomechanics; Body Fluids; Bone Density; Bone Regeneration; Bone Tissue; Bone remodeling; Cellular Morphology; Clinical; Committee Members; Dental; Dental Implants; Diagnosis; Disease; Doctor of Philosophy; Dose; Dysplasia; Encapsulated; Ensure; Fracture; Genetic; Goals; Homeostasis; Immunohistochemistry; Implant; Implantation procedure; Intervention; Jaw; Knowledge; Lead; Learning; Maxilla; Mechanics; Mentors; Michigan; MicroRNAs; Modeling; Molecular; Monitor; Mus; Operative Surgical Procedures; Oral Surgical Procedures; Orthopedics; Osseointegration; Osteogenesis; Osteogenesis Imperfecta; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phenotype; Play; Positioning Attribute; Process; Property; Quality of life; Regenerative Medicine; Regimen; Regulation; Research; Research Project Grants; Sampling; Schedule; School Dentistry; Scientist; Serum; Severity of illness; Short-Term Course; Specificity; Surgeon; Techniques; Testing; Time; Training; Trauma; Treatment Protocols; Treatment outcome; Universities; Wild Type Mouse; Work; antagonist; base; bisphosphonate; bone; bone healing; bone mass; bone metabolism; career; clinical application; craniofacial; differential expression; exosome; experimental study; healing; improved; innovation; long bone; microRNA biomarkers; minimally invasive; mouse model; novel strategies; oral surgery specialty; orofacial; personalized medicine; prevent; professor; response; skeletal; skills; support tools; surgery outcome; tool; treatment response; treatment strategy

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.

项目概要/摘要 成骨不全是一种遗传性发育不良，其特征是骨质疏松，骨折增加， 骨密度目前的OI管理主要依赖于长期的抗吸收治疗， 骨折，但可能会干扰正常的颌骨愈合。硬化蛋白抗体是治疗骨质疏松症的一种新策略 （SclAb），其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的生物力学性能，长期连续给药 通过增加Wnt拮抗剂表达迅速降低骨形成反应。循环SclAb治疗 基于长骨研究，在无抗体期恢复骨形成反应，因此知之甚少 这种策略如何影响颌骨和种植体骨整合（骨愈合）。成功的植入物稳定性 （初级愈合）和骨整合（长期愈合）取决于良好的骨密度。因此，预测 颌骨骨密度在种植体植入前后的OI中，临床上需要生物标记SclAb诱导 合成代谢作用。MicroRNA（miRNAs）作为OI的生物标志物的用途是有吸引力的。发现在以下方面发挥关键作用： 骨稳态相关通路的调节，骨重建相关的miRNA可能取代 目前的非特异性骨密度诊断工具，从而为OI提供个性化的医学方法 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 其诱导并维持颌骨形成反应及其对骨整合的作用。目标2： 确定检测或预测SclAb治疗结果的骨重塑相关miRNA组，以指导 种植体放置决定。该提案的结果将提供SclAb治疗时间表， 诱导和维持最佳的骨合成代谢作用，而不影响愈合和 合成代谢和再吸收阶段，可用于关联SclAb对牙齿和骨代谢的影响， 骨科治疗决策和低骨量患者的长期疾病监测。 候选人坚定地致力于发展有效的，临床适用的口面骨的职业生涯 再生策略，以改善低骨量障碍患者的生活质量。导师， 顾问委员会成员和密歇根大学口腔颌面外科系 牙科学院大力支持候选人和她的职业和研究目标。她目前持有A 作为一个助理教授，她的博士研究项目有20%的时间受到保护。拟议 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 过渡到独立作为一个外科医生，科学家，重点是转化颅面再生 药