TRANCE REGULATION OF CHONDROCYTE MATURATION

描述(改编自《调查员摘要》)：该项目将 调查生长因子幻觉直接调节的假说 阑尾和颅面软骨的成熟与骨生长 以骨质疏松大鼠和小鼠骨骼为模型系统。催眠是必需的 骨吸收，但最近的报告和提供的初步数据 在这里，它可能还调节骨骼生长和软骨细胞 (软骨内)长骨生长板的成熟，缝线 (膜内)颅面骨骼的发育和生长 胶原蛋白基因在这两个位点发生切换。因为独特的生长板 无牙骨质疏松大鼠的软骨营养不良及恍惚状态 敲除小鼠，以及该区域催眠受体RANK的存在 在受恍惚基因敲除突变影响最大的生长板中， 以下是假设：恍惚直接调节软骨细胞进程 在无牙大鼠所处的增殖期和肥大期 事实是一种自然发生的恍惚状态丧失功能突变，而这种恍惚状态 信号不依赖于IHH/PTHrP级联的生长调节。三 本文提出了检验这些假说的具体目标。在特定目标1中，正常 和无牙大鼠昏迷将被克隆和测序，蛋白质水平 测量和测试受体结合活性以排除或排除突变 影响无牙大鼠的催眠功能。《特定目标2：恍惚》 软骨细胞在培养过程中的结合及其信号转导 效果(IKB、PKB、c-src的磷酸化/活性)将在 能影响跖骨软骨细胞的生长和凋亡 文化。已知的生长板调节剂和胶原蛋白在龙虾中的表达 将测量颅骨中的骨骼和胶原类型，以评估其程度 而突变会扰乱它们。在具体目标3中，体内研究将 测定两者生长板中的细胞增殖和细胞死亡 突变以了解组织扭曲的细胞基础。恍惚状态 可能会在软骨培养系统中找到用途。骨骺软骨发育不良或 骨生长(四肢或面部畸形)和新陈代谢的其他缺陷可能是 是否影响药物或基因治疗的新潜在点 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.