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.

项目摘要/摘要 成骨不肠是一种遗传发育不良，其特征是骨骼脆性，骨骼骨折增加和低 骨密度。当前的OI管理主要依赖于长期的反感应治疗 骨折，但可能会干扰正常的下颌骨愈合。 OI治疗的新型策略是硬化蛋白抗体 （SCLAB），这会诱导强大的合成代谢反应以增加骨密度。尽管Sclab增加了骨头 形成并显着改善生物力学长骨特性，长期连续给药 通过增加Wnt拮抗剂表达来迅速降低骨形成反应。自行车治疗 随着无抗体时期的恢复基于长骨研究的骨形成反应，鲜为人知 该策略如何影响下颌骨和植入骨整合（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，要预测 植入物放置前后OI中的下颌骨密度，存在生物标记Sclab诱导的临床需求 合成代谢效应。将microRNA（miRNA）用作OI的生物标志物很有吸引力。发现在 骨体内平衡相关途径的调节，与骨建模相关的miRNA可能会取代 当前的非特异性骨密度诊断工具，导致了OI的个性化医学方法 治疗管理。这项研究有2个目标。目标1：阐明最佳SCLAB周期治疗方案 这会导致和维持颚骨的形成反应及其对骨整合的影响。目标2：到 确定检测或预测SCLAB治疗结果以引导的骨骼模型相关的miRNA面板 植入式安置决策。该提案的结果将提供SCLAB治疗时间表 诱导和维持最佳骨合成代谢作用，而不会影响愈合和miRNA面板 合成代谢阶段，可用于将SCLAB对牙齿代谢的影响相关联 低骨量患者的骨科治疗决策和长期疾病监测。 候选人坚定地致力于发展有效的，临床上适用的口面骨骼 更高骨质疾病患者生活质量的再生策略。她的导师， 咨询委员会成员以及密歇根大学的口腔和颌面外科系 牙科学校强烈支持候选人以及她的职业和研究目标。她目前拥有一个 她的博士学位研究项目的助理教授的位置为20％。提议 实验和教学工作将使她拥有独特的跨学科技能，使她能够 过渡到独立的外科医生科学家，重点是转化颅面再生 药品。