PPAR ACTIVATION IN GROWTH PLATE CHONDROCYTES

儿童肥胖症是一个迅速增长的问题，现在每四个儿童中就有一个面临长期健康问题。最近在分子水平上理解脂肪形成和脂肪代谢的进展揭示了核激素受体家族的存在，该家族将营养信号与基因表达的控制联系起来，并在高脂肪饮食中被诱导或激活。这些分子被称为过氧化物酶体增殖物激活受体(PPAR)，也在骨和软骨中表达，并在PPAR和TRS共表达的细胞中干扰甲状腺激素受体(TRR)介导的基因转录。鉴于正常的软骨内成骨需要过氧化体功能，而且甲状腺激素在生长板的骨骼成熟调节中起核心作用，因此有理由问在生长板软骨细胞中，TRR和PPAR介导的转录调控之间是否存在串扰。生长板细胞中TR和PPAR信号通路之间的串扰可能对儿童肥胖相关髋关节疾病股骨头骨盆滑脱(SCFE)的病因有直接的临床意义。这一建议将检验PPAR是生长板软骨细胞中可诱导的基因转录抑制因子的假说。这项工作的具体目的是：1)记录PPAR亚型在生长板中的表达，并建立PPAR是否与TRs在单个生长板软骨细胞中共表达；2)确定PPAR激活剂暴露于生长板软骨细胞是否导致这些细胞中PPAR表达的诱导和PPAR介导的基因转录的激活；3)表征PPAR与生长板软骨细胞中TRs和RXRs的分子相互作用，并描述这些相互作用对TRR介导的基因转录的影响；以及4)确定PPAR激活在甲状腺激素诱导的生长板细胞生长停滞和终末分化中的作用。

Childhood obesity is a rapidly growing concern which now threatens one in four children with long-term health problems. Recent advances in the understanding of adipogenesis and lipid metabolism at the molecular level have revealed the existence of a family of nuclear hormone receptors which link nutritional signals to the control of gene expression, and are induced or activated in response to a high fat diet. These molecules, termed peroxisome proliferator activated receptors (PPARs), are also expressed in bone and cartilage, and interfere with thyroid hormone receptor (TR) mediated gene transcription in cells in which PPARs and TRs are co-expressed. Given that peroxisomal function is required for normal endochondral ossification, and that thyroid hormone lays a central role in regulating skeletal maturation at growth plate, it is reasonable to ask if crosstalk may exist between TR and PPAR mediated transcriptional regulation in growth plate chondrocytes. Crosstalk between the TR and PPAR signaling pathways in growth plate cells may have direct clinical implication regarding the etiology of an obesity-related hip disease in children, slipped capital femoral epiphysis (SCFE). This proposal will test the hypothesis that PPARs are inducible repressors of TR mediated gene transcription i growth plate chondrocytes. The specific aims this work are: 1) to document the expression of PPAR isoforms in the growth plate and to establish if PPARs are co-expressed with TRs in individual growth plate chondrocytes; 2) to determine if exposure of growth plate chondrocytes to PPAR activators results in induction of PPAR expression and activation of PPAR-mediated gene transcription in these cells; 3) to characterize the molecular interactions of PPARs with TRs and RXRs in growth plate chondrocytes and describe the effect of these interactions on TR-mediated gene transcription; and 4) to define the effects of PPAR activation on thyroid hormone-induced growth arrest and terminal differentiation of growth plate cells.