CRANIAL VS APPENDICULAR SKELETAL REPAIR MECHANISMS

骨骼发育需要细胞规范、迁移、增殖和分化程序的精确协调，这些程序受到组织层和细胞外基质之间相互作用的调节。许多相同的事件发生在成人骨修复过程中。然而，尚不清楚骨骼愈合过程在多大程度上是骨骼发育程序的重演。这项研究的目标是阐明调节颅骨修复的分子和细胞机制，重点是下颌骨。基本假设是成人组织通过使用胎儿骨骼生成程序来愈合。提出以下具体目标。 (1)通过组织学和分子手段确定颅骨中关键软骨细胞和成骨细胞特异性基因产物的时空分布。 (2)确定下颌骨修复调节机制。在这个目标中，骨骼将被允许通过主要意图（膜内骨化）愈合，并且似乎调节颅骨骨骼组织的分子的表达和功能将受到干扰。 (3)通过遗传和生化手段确定扰乱骨发育对颅骨骨骼组织的影响。明胶酶 B 缺失小鼠将用于研究明胶酶 B 在调节下颌骨形成中的作用。由于血管生成延迟，明胶酶 B 小鼠的生长板骨化模式异常。这些实验将评估下颌形态发生和长骨发育之间的相似性和差异。这些研究可能揭示颅骨骨骼组织的形成和修复之间，或颅骨骨骼组织和长骨的修复之间的根本差异。长期目标是利用这些信息开发基于生物学的疗法，用于治疗由创伤和疾病引起的骨骼畸形和缺陷。

Skeletal development requires an exquisite coordination of programs for cell specification, migration, proliferation and differentiation that are regulated by interactions between tissue layers and the extracellular matrix. Many of the same events occur during adult bone repair. However, it is unclear to what extent the process of skeletal healing is a recapitulation of the skeletal development program. The goal of this research is to elucidate the molecular and cellular mechanisms regulating cranial skeletal repair, with a focus on the mandible. The underlying hypothesis is that adult tissues heal by using the fetal skeletogenic program. The following specific aims are propose. (1) Determine the spatial and temporal distribution of key chondrocyte- and osteoblast-specific gene products in the cranial skeleton by histological and molecular means. (2) Determine the mechanisms regulation repair in the mandible. In this aim, bones will be allowed to heal by primary intention (intramembranous ossification), and the expressions and functions of molecules that appear to regulate cranial skeletal tissues will be perturbed. (3) Determine the effects on cranial skeletal tissues of perturbing bone development by genetic and biochemical means. The gelatinase-B null mouse will be used to study the role of gelatinase B in regulation of mandibular bone formation. Gelatinase B mice have abnormal pattern of growth plate ossification due to a delay in angiogenesis. These experiments will assess similarities and differences between mandibular morphogenesis and long bone development. These studies may uncover fundamental differences between formation and repair of cranial skeletal tissues, or between the repair of cranial skeletal tissues and long bones. The long term goal is to use this information to develop biologically based therapies for the treatments of skeletal deformities and defects cause by trauma and disease.