Cellular and Mechanical Mechanisms Regulating Mandibular Distraction Osteogenesis

调节下颌牵张成骨的细胞和机械机制

基本信息

批准号：
9463620
负责人：
MICHAEL T LONGAKER
金额：
$ 37.49万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9463620
关键词：
Address Anatomy Animal Model Biology Biomechanics Blood Circulation Bone Regeneration Bone Tissue Bone Transplantation Bone callus Cell Differentiation process Cells Cephalic Characteristics Chimerism Complex Confocal Microscopy Controlled Environment Cornea Defect Deformity Dental Development Dissection Distraction Osteogenesis Elements Endosteum Epithelial Excision Face Fluorescence Fluorescence-Activated Cell Sorting Focal Adhesion Kinase 1 Focal Adhesions Freezing Genetic Goals Harvest Health Expenditures Histologic Impairment In Vitro Incisor Injections Knockout Mice Knowledge Label Limb structure Malocclusion Mandible Mandibular distraction Mandibulofacial Dysostosis Manuscripts Mechanics Mediating Mesenchyme Methods Molecular Morbidity - disease rate Mus Natural regeneration Neurologic Operative Surgical Procedures Osteogenesis Osteotomy Parabiosis Pathway interactions Patients Periosteum Plant Roots Play Population Process Protocols documentation Publishing Regenerative response Reporter Research Research Proposals Robin bird Role Secondary to Signal Pathway Signal Transduction Site Skeleton Source Stem cells Stimulus Tamoxifen Techniques Therapeutic TimeLine Tissue Engineering Tissues Tooth root structure Transgenic Mice Transplanted tissue Trauma biomaterial compatibility bone cell determination cellular transduction congenital anomaly craniofacial craniofacial microsomia disability distraction improved in vivo inhibitor/antagonist mechanical force mechanotransduction mouse model novel novel strategies osteogenic peripheral blood progenitor reconstruction recruit response skeletal small molecule inhibitor stem success tool trafficking treatment choice tumor

项目摘要

Project Summary Craniofacial skeletal deficiencies involving the mandible, midface, and cranial vault result in a wide range of disabilities including severe airway compromise, malocclusion, inadequate corneal protection, and neurological impairment. Secondary to trauma, tumor resection, or developmental anomalies, these deformities represent a significant reconstructive challenge and account for over $1 billion in annual health care expenditures. While surgical techniques integrating conventional osteotomies with autogenous bone and/or synthetic graft materials can be successful, limitations in donor site morbidity, biocompatibility, and osteoconductivity still remain. As an alternative approach, distraction osteogenesis (DO) offers the ability to promote endogenous bone formation across a mechanically controlled environment, providing anatomical and functional replacement of deficient tissue. The application of DO to the craniofacial skeleton has revolutionized the treatment of many congenital and acquired defects, and for many patients with mandibular deficiency associated with Pierre-Robin sequence, Treacher Collins syndrome, and craniofacial microsomia, distraction osteogenesis has become the treatment choice. We have developed a novel model of mouse mandibular distraction which allows for lineage tracing of cellular contribution to the regenerate and genetic dissection of biomechanical force transduction regulating cell differentiation during guided bone formation. Findings from this proposal will deepen our knowledge of how progenitor cells localize to the regenerate and enhance our understanding of craniofacial distraction. The identification of the cellular source within the DO regenerate, the timeline for progenitor cell response, and determination of how these cells transduce physical stimuli to enact a regenerative response may all facilitate development of improved distraction protocols. Findings from this proposal may provide new and effective strategies for reconstruction of the craniofacial skeleton.

项目概要涉及下颌骨、中面部和颅顶的颅面骨骼缺陷会导致多种残疾，包括严重气道受损、咬合不正、角膜保护不足和神经功能障碍。这些畸形继发于创伤、肿瘤切除或发育异常，是重大的重建挑战，每年造成的医疗保健支出超过 10 亿美元。虽然将传统截骨术与自体骨和/或合成移植材料相结合的外科技术可以取得成功，但供体部位发病率、生物相容性和骨传导性方面的局限性仍然存在。作为一种替代方法，牵引成骨 (DO) 能够在机械控制的环境中促进内源性骨形成，从而提供缺陷组织的解剖学和功能性替代。 DO在颅面骨骼中的应用彻底改变了许多先天性和后天性缺陷的治疗，对于许多与Pierre-Robin序列相关的下颌骨缺损、Treacher Collins综合征和颅面微小症患者来说，牵引成骨已成为治疗选择。我们开发了一种新型的小鼠下颌牵引模型，可以对引导骨形成过程中调节细胞分化的生物力学力转导的再生和遗传解剖的细胞贡献进行谱系追踪。该提案的研究结果将加深我们对祖细胞如何定位再生的认识，并增强我们对颅面牵引的理解。 DO 再生中细胞来源的识别、祖细胞反应的时间线以及这些细胞如何转导物理刺激以产生再生反应的确定都可能有助于开发改进的分散方案。该提案的研究结果可能为颅面骨骼的重建提供新的有效策略。