CRANIAL VS APPENDICULAR SKELETAL REPAIR MECHANISMS

骨骼发育需要精确协调细胞规格、迁移、增殖和分化的程序，这些程序受组织层和细胞外基质之间的相互作用调节。许多相同的事件发生在成人骨骼修复过程中。然而，目前尚不清楚骨骼愈合过程在多大程度上是骨骼发育计划的重演。这项研究的目的是阐明调控颅骨修复的分子和细胞机制，重点是下颌骨。基本的假设是，成人组织通过胎儿骨骼发育程序进行修复。提出了以下具体目标。(1)用组织学和分子生物学方法确定关键的软骨细胞和成骨细胞特异性基因产物在颅骨中的时空分布。(2)确定下颌骨的修复机制。在这个目标中，骨骼将被允许通过主要意图(膜内成骨)愈合，而似乎调节颅骨组织的分子的表达和功能将受到干扰。(3)从遗传学和生物化学的角度确定干扰骨发育对颅骨组织的影响。明胶酶B缺失小鼠将被用来研究明胶酶B在调控下颌骨形成中的作用。明胶酶B小鼠由于血管生成延迟而出现生长板骨化的异常模式。这些实验将评估下颌形态发生和长骨发育之间的异同。这些研究可能揭示颅骨组织的形成和修复之间的根本区别，或者颅骨组织和长骨修复之间的根本区别。长期目标是利用这些信息开发基于生物的治疗方法，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.