TERMINAL DIFFERENTIATION OF GROWTH PLATE CHONDROCYTES

生长板软骨细胞的末端分化

基本信息

批准号：
6349958
负责人：
Robert Tracy Ballock
金额：
$ 12.12万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-02-01 至 2002-01-31
项目状态：
已结题

项目摘要

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.

描述（改编自申请人的摘要）：甲状腺缺乏症儿童体内的激素会导致骨骼成熟延迟、紊乱生长板软骨柱的破坏和分化受损生长板软骨细胞转变为肥大细胞。这些异常临床上常表现为严重的生长迟缓和机械性发育迟缓。髋部生长板衰竭（股骨头滑脱骨骺）。尽管在理解系统性方面取得了令人兴奋的进展激素和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生长和发育产生这些深远的影响仍然存在一个谜。越来越多的证据表明，全身激素和一般的肽生长因子，特别是甲状腺激素，可能调节细胞生长和分化，部分通过控制细胞周期。化学定义的生长板软骨细胞模型已经开发出分化能力，不仅非常敏感甲状腺激素，而且还导致软骨细胞的形态发生柱状图案类似于体内生长板。该模型将是用于确定甲状腺激素是否调节之间的转变软骨细胞生长和分化，部分通过抑制细胞在细胞周期中的进展。本次活动的具体目标项目有： 1）定义甲状腺激素在调节甲状腺激素中的作用从细胞生长到细胞分化的转变化学定义的生长板软骨细胞分化模型； 2）到表征细胞周期对甲状腺激素诱导的终末期的反应该系统的微分； 3) 过表达特定的细胞周期通过瞬时转染，将生长板软骨细胞中的蛋白质确定它们对甲状腺激素信号传导的影响。