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Regulation of Gene Expression in Cartilage

软骨基因表达的调控

基本信息

批准号：
7847192
负责人：
LINDA J SANDELL
金额：
$ 1.61万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-10 至 2010-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7847192
关键词：
Address Adipose tissue Adult Alternative Splicing Applications Grants Binding Biological Models CCAAT-Enhancer-Binding Proteins Cartilage Cell Line Cells Chick Embryo Chondrocytes Chondrogenesis Clinical Collaborations Collagen Gene Data Degenerative polyarthritis Development Disease Dorsal EWS/FLI 1 Type 1 antisense oligonucleotide Embryo Event Excision Exons Extracellular Matrix Family member Gene Expression Gene Expression Regulation Genes Genetic Transcription Grant Health In Vitro Inflammation Inflammatory Interleukin-1 Intervertebral disc structure Laboratories Length Maintenance Mediating Mesenchymal Messenger RNA NF-kappa B Nuclear Nuclear RNA Osteogenesis Play Process Procollagen Production Protein Biosynthesis Protein Isoforms Proteins RNA Splicing RNA-Binding Proteins Regulation Reporter Role Signal Transduction Skeletal Development Staging Stem cells System TFAP2A gene Testing Tissue Engineering Trans-Activators Transcription Process Translations Type II Procollagen Undifferentiated Work Wound Healing Xenopus adult stem cell bone morphogenetic protein 2 bone morphogenetic protein 4 cartilage development cytokine enhancer-binding protein AP-2 improved in vitro testing in vivo insight mRNA Precursor notochord novel strategies repaired response transcription factor

项目摘要

DESCRIPTION (provided by applicant): Understanding the mechanisms that control chondrogenesis is of major clinical importance for improving tissue engineering strategies that can be applied to repair cartilage during osteoarthritis, for example. Studies proposed for the grant renewal period are focused on deciphering the regulation chondrogenesis at the level of gene transcription, precursor messenger RNA (pre-mRNA) alternative splicing and protein synthesis. The following three Specific Aims will directly address these aspects of cartilage development: 1) Investigate the role of transcription factors during chondrogenesis, specifically AP-2, dEF-1 and C/EBP; 2) Investigate the regulation of the type II procollagen pre-mRNA switch that occurs during chondrogenesis and 3) Determine the function of the developmentally-expressed type IIA procollagen protein isoform in vivo. Combined data from these Specific Aims will provide unique insight into the regulation of chondrogenesis as it is becoming apparent that processes of transcription, RNA splicing and translation are tightly coordinated. We also plan to study mechanisms important for cartilage maintenance and repair as described in the fourth Specific Aim: 4) Investigate the mechanism of IL-1b and TNF-a induction of BMP-2 in adult chondrocytes. Processes that occur during chondrogenesis are believed to be recapitulated during tissue repair under conditions of cartilage degradation. Therefore, the final Specific Aim in combination with the first three Specific Aims focused on chondrogenesis will provide invaluable information into the maintenance of cartilage health. The predominant experimental approach to these topics will be to use in vitro systems of chondrogenesis utilizing the ATDC5 cell line and adult stem cells isolated from adipose tissue to investigate state-specific differentiation events. Regulatory factors will be tested by over expression and inhibition studies and correlated with expression in vivo.

描述（由申请人提供）：了解控制软骨形成的机制对于改善组织工程策略具有重要的临床意义，例如，组织工程策略可用于骨关节炎期间修复软骨。资助更新期的研究重点是在基因转录、前体信使RNA（pre-mRNA）选择性剪接和蛋白质合成水平上破译软骨形成的调控。以下三个具体目标将直接解决软骨发育的这些方面：1）研究软骨形成过程中转录因子的作用，特别是AP-2、dEF-1和C/EBP; 2）研究软骨形成过程中II型前胶原前mRNA转换的调节; 3）确定体内发育表达的IIA型前胶原蛋白亚型的功能。来自这些特定目标的组合数据将为软骨形成的调控提供独特的见解，因为转录，RNA剪接和翻译过程是紧密协调的。我们还计划研究软骨维护和修复的重要机制，如第四个具体目标所述：4）研究IL-1b和TNF-α诱导成人软骨细胞中BMP-2的机制。在软骨形成过程中发生的过程被认为是在软骨降解条件下的组织修复过程中重现的。因此，最终的具体目标与前三个具体目标相结合，专注于软骨形成，将为维护软骨健康提供宝贵的信息。这些主题的主要实验方法将是使用体外软骨形成系统，利用ATDC 5细胞系和从脂肪组织分离的成体干细胞来研究状态特异性分化事件。调节因子将通过过表达和抑制研究进行测试，并与体内表达相关。