Regulation of Gene Expression in Cartilage

软骨基因表达的调控

• 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
• 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

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）：例如，了解控制软骨形成的机制对于改善组织工程策略的重要性至关重要，例如，可以在骨关节炎期间用于修复软骨。针对授予续签期提出的研究集中于在基因转录水平，前体信使RNA（PRE-MRNA）替代剪接和蛋白质合成的水平上解密软骨形成。以下三个特定目标将直接解决软骨发展的这些方面：1）研究转录因子在软骨生成过程中的作用，特别是AP-2，DEF-1和C/C/EBP； 2）研究在软骨发生过程中发生的II型Procollagen前MRNA开关的调节，3）确定体内发育表达的IIA型Procollagen蛋白同工型的功能。来自这些特定目标的组合数据将为软骨发生的调节提供独特的见解，因为显而易见的是，转录，RNA剪接和翻译的过程紧密地协调。我们还计划研究对软骨维持和维修重要的机制，如第四个具体目的所述：4）研究成年软骨细胞中IL-1B和TNF-A诱导BMP-2的机制。在软骨降解条件下，在组织修复过程中会概括软骨发生过程中发生的过程。因此，结合前三个针对软骨生成的特定目的的最终特定目标将为维持软骨健康提供宝贵的信息。这些主题的主要实验方法将是利用从脂肪组织分离的ATDC5细胞系和成年干细胞使用软骨发生的体外系统来研究状态特异性分化事件。调节因素将通过过度表达和抑制研究测试，并与体内表达相关。

项目成果

Biosynthesis and processing of bovine cartilage link proteins.

牛软骨连接蛋白的生物合成和加工。

• 发表时间: 1990
• 期刊: The Journal of biological chemistry
• 作者: Hering,TM;Sandell,LJ
• 通讯作者: Sandell,LJ

Site-1 protease is essential for endochondral bone formation in mice.

• DOI: 10.1083/jcb.200708092
• 发表时间: 2007-11-19
• 期刊: The Journal of cell biology
• 作者: Patra D;Xing X;Davies S;Bryan J;Franz C;Hunziker EB;Sandell LJ
• 通讯作者: Sandell LJ

Biosynthesis of small proteoglycan II (decorin) by chondrocytes and evidence for a procore protein.

软骨细胞生物合成小蛋白多糖 II（核心蛋白聚糖）和 procore 蛋白的证据。

• 发表时间: 1991
• 期刊: The Journal of biological chemistry
• 作者: Sawhney,RS;Hering,TM;Sandell,LJ
• 通讯作者: Sandell,LJ

Resistin induces expression of proinflammatory cytokines and chemokines in human articular chondrocytes via transcription and messenger RNA stabilization.

• DOI: 10.1002/art.27473
• 发表时间: 2010-07
• 期刊: ARTHRITIS AND RHEUMATISM
• 作者: Zhang, Zhiqi;Xing, Xiaoyun;Hensley, Gretchen;Chang, Li-Wei;Liao, Weiming;Abu-Amer, Yousef;Sandell, Linda J.
• 通讯作者: Sandell, Linda J.

Resistin stimulates expression of chemokine genes in chondrocytes via combinatorial regulation of C/EBPβ and NF-κB.

• DOI: 10.3390/ijms151017242
• 发表时间: 2014-09-26
• 期刊: International journal of molecular sciences
• 影响因子: 5.6
• 作者: Zhang Z;Zhang Z;Kang Y;Hou C;Duan X;Sheng P;Sandell LJ;Liao W
• 通讯作者: Liao W