Translational Control in Cartilage Biology

软骨生物学中的转化控制

基本信息

批准号：
9731119
负责人：
Victoria Kolupaeva
金额：
$ 14.9万
依托单位：
NEW YORK UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-25 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9731119
关键词：
Translational Control Cartilage Biology

项目摘要

PROJECT SUMMARY Chondrocytes are the cartilage primary cells responsible for the pattering and growth of much of the skeleton, particularly the long bones and cartilage tissue. Formation and remodeling of cartilage requires efficient synthesis of extracellular matrix proteins and equally efficient expression of matrix-degrading enzymes. Imbalanced chondrocyte homeostasis leads to a variety of musculoskeletal disorders from cartilage degeneration in the joint in osteoarthritis (OA) to inadequate chondrocyte proliferation in the growth plate in achondroplasia. Our recent work revealed that regulation of mRNA translation plays a crucial role in chondrocyte homeostasis, as we demonstrated the importance of 4E-BP (eukaryotic initiation factor (eIF) 4E Binding Protein, a repressor of cap-dependent translation) in FGF-induced growth arrest in proliferating chondrocytes as well as in sustaining healthy articular cartilage. By binding to the critical translation initiation factor eIF4E, which is required to recognize the cap structure of eukaryotic mRNA and assemble a multi- subunit complex called eIF4F that recruits the 40S ribosome, 4E-BP functions to repress translation of select capped mRNAs that are eIF4F-dependent. In the first part of this application we will elucidate the mechanism of FGF-induced 4E-BP activation in chondrocytes. To understand further the complex post-transcriptional gene control upon FGF signaling in chondrocytes we plan to determine a role of Patl1 (Protein PAT1 homolog 1) – a protein involved in mRNA stability. We identified this protein in our phosphoproteomics analysis as FGF responsive and necessary for mediating FGF inhibitory response. We will investigate the mechanisms that govern translation control during chondrocyte differentiation focusing on the proper balance between osteo- adipo- and chondrogenesis. In the last part of our application chondrocytes we will investigate how dysregylation of eIF4F impacts global mRNA translation profile of OA cartilage and investigate if modulation of the eIF4F activity can reverse OA like phenotype in vitro and in vivo.

项目摘要软骨细胞是负责大部分的模式和生长的软骨主要细胞骨骼，尤其是长骨和软骨组织。软骨的形成和重塑需要有效合成细胞外基质蛋白和基质降解的同样有效表达酶。软骨细胞体内平衡导致软骨的多种肌肉骨骼疾病关节骨关节炎（OA）的变性，以使生长板中的软骨细胞增殖不足肌浮肿。我们最近的工作表明，对mRNA翻译的调节在软骨细胞稳态，正如我们证明了4E-BP（真核倡议因子（EIF）4E的重要性）结合蛋白，在FGF诱导的增殖中引起的生长停滞的cap依赖性翻译的复制品软骨细胞以及维持健康的关节软骨。通过与关键翻译启动结合因子EIF4E，必须识别真核mRNA的帽结构并组装多个亚基复合物称为EIF4F，募集40S核糖体，4E-BP函数以反映SELECT的翻译依赖于EIF4F的mRNA。在本应用程序的第一部分中，我们将阐明机制 FGF诱导的软骨细胞中的4E-BP激活。进一步了解复杂的转录后基因控制软骨细胞中FGF信号传导我们计划确定patl1的作用（蛋白质PAT1同源1） - a 参与mRNA稳定性的蛋白质。我们在磷酸蛋白质组学分析中确定了这种蛋白质为FGF 响应敏感和介导FGF抑制反应所必需的。我们将研究的机制控制软骨细胞分化过程中的翻译控制，重点是骨之间的适当平衡脂肪和软骨生成。在我们应用程序软骨细胞的最后一部分中，我们将调查如何 EIF4F的差苯甲酸影响OA软骨的全局mRNA翻译曲线，并调查是否调制 EIF4F活性可以在体外和体内逆转OA，例如表型。