PPAR ACTIVATION IN GROWTH PLATE CHONDROCYTES

生长板软骨细胞中的 PPAR 激活

• 批准号: 6368201
• 负责人: Robert Tracy Ballock
• 金额: $ 30.6万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6368201
• 关键词: bone morphogenetic proteins; cell differentiation; cell proliferation; chondrocytes; collagen; gel mobility shift assay; gene expression; gene induction /repression; gene interaction; genetic transcription; hormone receptor; immunocytochemistry; intermolecular interaction; laboratory rat; messenger RNA; northern blottings; peroxisome proliferator activated receptor; polymerase chain reaction; protein isoforms; thyroid hormones; transfection; western blottings

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.

儿童肥胖是一个迅速增长的问题，目前威胁着四分之一儿童的长期健康问题。在分子水平上对脂肪生成和脂质代谢的理解的最新进展揭示了核激素受体家族的存在，该受体将营养信号与基因表达的控制联系起来，并响应高脂肪饮食而被诱导或激活。 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，并干扰 PPAR 和 TR 共表达的细胞中甲状腺激素受体 (TR) 介导的基因转录。鉴于正常软骨内骨化需要过氧化物酶体功能，并且甲状腺激素在调节生长板骨骼成熟中发挥核心作用，因此有理由询问生长板软骨细胞中 TR 和 PPAR 介导的转录调节之间是否存在串扰。 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骺滑脱 (SCFE) 的病因学具有直接的临床意义。该提案将检验以下假设：PPAR 是生长板软骨细胞中 TR 介导的基因转录的诱导型阻遏物。 这项工作的具体目标是：1）记录生长板中 PPAR 同工型的表达，并确定 PPAR 是否与个体生长板软骨细胞中的 TR 共表达； 2)确定生长板软骨细胞暴露于PPAR激活剂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) 表征生长板软骨细胞中 PPAR 与 TR 和 RXR 的分子相互作用，并描述这些相互作用对 TR 介导的基因转录的影响； 4) 确定 PPAR 激活对甲状腺激素诱导的生长停滞和生长板细胞终末分化的影响。