TERMINAL DIFFERENTIATION OF GROWTH PLATE CHONDROCYTES

描述(改编自申请者摘要)：甲状腺功能不全 儿童激素导致骨骼成熟延迟，组织紊乱 生长板的软骨柱，分化受损 生长板软骨细胞转化为肥大细胞。这些异常现象 临床上通常表现为严重的生长迟缓和机械性 髋部生长板失效(股骨头滑脱 附生植物)。尽管在理解如何系统性方面取得了令人兴奋的进展 激素和多肽生长因子调节生长和分化 靶组织的数量，甲状腺激素的分子机制 对骨骼的生长和发育产生了这些深刻的影响 一个谜。越来越多的证据表明，全身荷尔蒙和 一般情况下，肽生长因子，特别是甲状腺激素，可能 调节细胞的生长和分化，部分是通过控制 细胞周期。生长板软骨细胞的化学定义模型 已经发展出了微分学，它不仅非常敏感 对甲状腺激素的作用，但也导致软骨细胞的形态发生 柱状图案类似于体内生长板。这款车型将是 用来确定甲状腺激素是否调节 软骨细胞的生长和分化，部分是通过抑制 细胞在整个细胞周期中的进程。这样做的具体目的是 项目是：1)确定甲状腺激素在调节 从细胞生长到细胞分化的过渡 生长板软骨细胞分化的化学模型；2) 甲状腺激素诱导终末的细胞周期反应特征 在这个系统中的分化；以及3)过度表达特定的细胞周期 生长板软骨细胞中的蛋白质，通过瞬时转染法 确定它们对甲状腺激素信号的影响。

DESCRIPTION (Adapted from the Applicant's Abstract): Deficiency of thyroid hormone in children results in delayed skeletal maturation, disorganization of the cartilage columns of the growth plates, and impaired differentiation of growth plate chondrocytes into hypertrophic cells. These abnormalities are often clinically manifested as severe growth retardation and mechanical failure of the growth plates of the hips (slipped capital femoral epiphyses). Despite exciting advances in the understanding of how systemic hormones and peptide growth factors regulate growth and differentiation in a number of target tissues, the molecular mechanisms by which thyroid hormone exerts these profound effects on bone growth and development have remained an enigma. Evidence is accumulating to suggest that systemic hormones and peptide growth factors in general, and thyroid hormone in particular, may regulate cell growth and differentiation, in part through control of the cell cycle. A chemically-defined model of growth plate chondrocyte differentiation has been developed which is not only exquisitely sensitive to thyroid hormone, but also results in morphogenesis of chondrocytes into a columnar pattern similar to the in vivo growth plate. This model will be used to determine if thyroid hormone regulates the transition between chondrocyte growth and differentiation, in part through inhibiting progression of cells through the cell cycle. The Specific Aims of this project are: 1) to define the role of thyroid hormone in regulating the transition from cell growth to cell differentiation in this chemically-defined model of growth plate chondrocyte differentiation; 2) to characterize the cell cycle response to thyroid hormone-induced terminal differentiation in this system; and 3) to overexpress specific cell cycle proteins in growth plate chondrocytes, by transient transfection, to determine their effect on thyroid hormone signalling.