Translational Control in Cartilage Biology. - Resubmission - 1

软骨生物学中的转化控制。

• 批准号: 8587414
• 负责人: Victoria Kolupaeva
• 金额: $ 36.02万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8587414
• 关键词: 70-kDa Ribosomal Protein S6 Kinases; Address; Animal Model; Apoptosis; Binding; Binding Proteins; Biology; Cartilage; Cataloging; Catalogs; Cell Proliferation; Cells; Chondrocytes; Complex; Data; Degenerative polyarthritis; Down-Regulation; Dwarfism; Employee Strikes; Enzymes; Epiphysial cartilage; Eukaryotic Initiation Factor-4E; Extracellular Matrix Proteins; Fibroblast Growth Factor; Gene Expression; Genes; Genetic Transcription; Growth; Growth Factor; Homeostasis; Human; In Vitro; Joints; Kinetics; Maintenance; Mediating; Messenger RNA; Modeling; Modification; Molecular; Musculoskeletal Diseases; Pathway interactions; Phosphorylation; Phosphotransferases; Play; Post-Translational Protein Processing; Process; Proliferating; Protein Biosynthesis; Protein Dephosphorylation; Protein Synthesis Inhibition; Proteins; Proteomics; Proto-Oncogene Proteins c-akt; Rattus; Regulation; Repression; Ribosomal Protein S6; Ribosomes; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Skeleton; Syndrome; System; TIMP1 gene; Testing; Tissue Inhibitor of Metalloproteinase-1; Tissues; Translating; Translation Initiation; Translational Regulation; Translations; Up-Regulation; base; bone; cartilage cell; cell type; design; genome-wide analysis; human FRAP1 protein; inhibitor/antagonist; long bone; new therapeutic target; novel therapeutics; protein activation; public health relevance; reconstitution; response; translation factor; treatment strategy

DESCRIPTION (provided by applicant): This proposal is focused on translation control in cartilage biology. Chondrocytes are the primary cells responsible for the growth and maintenance of bones and cartilage tissue. Deregulation of chondrocyte homeostasis gives rise to a variety of musculoskeletal disorders, including osteoarthritis (OA). While many studies have focused on transcriptional mechanisms involved in regulation of chondrocytes proliferation and differentiation, the role of translation control in these processes has never been addressed. It is well established, that chondrocytes proliferation and differentiation are regulated by a number of signaling molecules and one of the central roles in these processes belongs to Fibroblast Growth Factors (FGFs). While in most cell types FGFs induce proliferation and protect from apoptosis, proliferating chondrocytes are distinct in their response to FGF, responding with growth inhibition. According to our preliminary data, protein synthesis is dramatically decreased in FGF-treated chondrocytes, a response that is opposite to well established stimulation of protein synthesis by growth factors in many other systems. Moreover, we were able to detect FGF-induced activation of eukaryotic Initiation Factor 4E Binding Protein (4E-BP) which is a known inhibitor of cap-dependent translation. While 4E-BP was also active in human articular chondrocytes, its activity was significantly lower in OA cartilage, indicating deregulation of translational apparatus under this pathological condition. This proposal aims to investigate the mechanism that mediates FGF-induced downregulation of protein synthesis in proliferating chondrocytes and regulation of protein synthesis during differentiation of chondrocytes. In the first part of this application we will investigate FGF-induced inhibition of protein synthesis in proliferative chondrocytes. We will determine the mechanism leading to this diverse response. The second part of our proposal will aim to identify specific pools of mRNAs that are actively translated under general repression of protein synthesis. We will employ ribosomal profiling to identify these mRNAs. The last part of the proposal will aim to determine the mechanism leading to activation of translation machinery in OA cartilage when compared to normal human cartilage. This project will provide basis for facilitating new specific targets in OA and other musculoskeletal disorders.

描述（由申请人提供）：该提案的重点是软骨生物学中的翻译控制。软骨细胞是负责骨骼和软骨组织生长和维持的主要细胞。软骨细胞稳态的放松管制会引起多种肌肉骨骼疾病，包括骨关节炎（OA）。尽管许多研究都集中在与软骨细胞增殖和分化有关的转录机制上，但翻译控制在这些过程中的作用从未得到解决。这是 良好的确定，软骨细胞增殖和分化受许多信号分子的调节，这些过程中的主要作用之一属于成纤维细胞生长因子（FGFS）。尽管在大多数细胞类型中，FGF会诱导增殖并免受细胞凋亡的保护，但增殖的软骨细胞对FGF的反应是不同的，并且会随着生长的抑制作用。根据我们的初步数据，在FGF处理的软骨细胞中，蛋白质合成急剧下降，这种反应与许多其他系统中生长因子对蛋白质合成的刺激相反。此外，我们能够检测FGF诱导的真核起始因子4E结合蛋白（4E-BP）的激活，这是已知的cap依赖性翻译抑制剂。尽管4E-BP在人类关节软骨细胞中也活跃，但在OA软骨中其活性显着降低，表明在这种病理状况下对转化装置的管制失调。该建议旨在研究介导FGF诱导的蛋白质合成下调的机制，并在软骨细胞分化过程中介导蛋白质合成和蛋白质合成的调节。 在本应用的第一部分中，我们将研究FGF诱导的增殖软骨细胞中蛋白质合成的抑制作用。我们将确定导致这种不同反应的机制。我们提案的第二部分将旨在确定在蛋白质合成的一般抑制下积极翻译的特定mRNA池。我们将采用核糖体分析来识别这些mRNA。该提案的最后一部分将旨在确定与正常的人软骨相比，导致OA软骨中翻译机械激活的机制。该项目将为促进OA和其他肌肉骨骼疾病的新特定目标提供基础。