TRANCE REGULATION OF CHONDROCYTE MATURATION

描述（改编自研究者摘要）：本项目将 研究生长因子TRANCE直接调节 软骨成熟和骨生长在肩胛骨和颅面 骨骼使用骨硬化大鼠和小鼠作为模型系统。需要TRANCE 但最近的报告和初步数据显示， 这使得它可能也调节骨生长和软骨细胞 （软骨内）长骨生长板的成熟，骨缝 （膜内）颅面骨骼的发育和生长， 两个位点的胶原基因转换。由于独特的生长板 软骨营养不良存在于无牙骨硬化大鼠和TRANCE 敲除小鼠，以及TRANCE受体RANK在该区域的存在 在受TRANCE敲除突变影响最大的生长板中， 以下假设：TRANCE直接调节软骨细胞进展 通过增殖和肥大阶段，无牙鼠所处的阶段 事实上是一种自然发生的TRANCE功能丧失突变， 信号传导独立于生长调节的Ihh/PTHrP级联。三 具体目标是测试这些假设。在特定目标1中，正常 和无牙大鼠TRANCE将被克隆和测序， 测量，并测试受体结合活性以排除突变 影响无牙大鼠的TRANCE功能。在具体目标2，TRANCE 与培养的软骨细胞的结合以及由此产生的信号转导 将测试效应（IkB、PKB、c-src的磷酸化/活性），沿着 其能够影响跖骨中软骨细胞的生长和凋亡 文化已知的生长板调节因子和胶原蛋白在长 将测量颅骨中的骨骼和胶原类型，以评估 突变会破坏它们在具体目标3中，体内研究将 确定两者生长板中的细胞增殖和细胞死亡 突变来理解组织变形的细胞基础。恍惚 可以在软骨培养系统中找到用途。骨骺软骨发育不良或 骨生长（肢体或面部畸形）和代谢中的其它缺陷可能 如果药理学或基因治疗的新潜力点 干预措施被发现。

DESCRIPTION (Adapted from the Investigator's Abstract): This project will investigate the hypothesis that the growth factor TRANCE directly regulates both cartilage maturation and bone growth in the appendicular and craniofacial skeleton using osteopetrotic rats and mice as model systems. TRANCE is required for bone resorption, but recent reports and the preliminary data presented herein, make it probable that it also regulates bone growth and chondrocyte maturation in the growth plates of (endochondral) long bones, suture development and growth in the (intramembranous) craniofacial skeleton, an collagen gene switching in both sites. Because of the unique growth plate chondrodystrophy present in the toothless osteopetrotic rat and the TRANCE knock-out mouse, and the presence of the TRANCE receptor, RANK, in the region of the growth plate most affected by the TRANCE knockout mutation, the following are hypothesized: TRANCE directly regulates chondrocyte progression through the proliferative and hypertrophic stages, that the toothless rat is in fact a naturally-occurring TRANCE loss-of-function mutation, and that TRANCE signaling is independent of the Ihh/PTHrP cascade of growth regulation. Three specific aims are presented to test these hypotheses. In Specific Aim 1, normal and toothless rat TRANCE will be cloned and sequenced, the protein level measured, and receptor-binding activity tested to rule in or out a mutation affecting TRANCE function in the toothless rat. In Specific Aim 2, TRANCE binding to chondrocytes in culture and the resultant signal transduction effects (phosphorylation/activity of IkB, PKB, c-src) will be tested, along with its ability to affect chondrocyte growth and apoptosis in metatarsal culture. Expression of known growth plate regulators and collagens in long bones and collagen types in the skull will be measured to assess the extent to which the mutations disrupt them. In Specific Aim 3, in vivo studies will determine cell proliferation and cell death in the growth plates of both mutations to understand the cellular basis for the tissue distortions. TRANCE may find uses in cartilage culture systems. Epiphyseal chondrodysplasias or other defects in bone growth (limb or facial deformities) and metabolism may be impacted if new potential points for pharmacological or gene therapy interventions are discovered.