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CONTROL OF CHONDROCYTE DIFFERENTIATION

软骨细胞分化的控制

基本信息

批准号：
7884588
负责人：
Benoit de Crombrugghe
金额：
$ 40.83万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-20 至 2012-04-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Our long term goal is to understand the transcriptional mechanisms of chondrocyte differentiation. Our previous work has demonstrated that Sox9 has a central role in chondrogenesis and is needed at multiple steps in the pathway of chondrocyte differentiation. Sox9 is initially needed to establish an osteochondroprogenitor; subsequently it is required for chondrogenic mesenchymal condensations. Sox9 is then needed for overt differentiation of chondrocytes, in part because Sox9 is required for expression of Sox5 and Sox6, which are needed for overt chondrocyte differentiation. Later in the pathway Sox9 still has another important role because it participates in the physiological inhibition of the maturation of chondrocytes into hypertrophic chondrocytes. In addition to its roles in the chondrocyte differentiation pathway, Sox9 is also needed for the differentiation of a small number of other cell lineages. Four specific aims are proposed to gain new insights in the mechanisms by which Sox9 and L-Sox5 control chondrocyte differentiation. The repertoire of genes controlled by Sox9 at two major steps in the chondrocyte differentiation program will first be identified. The hypothesis will also be tested whether Sox9 controls the expression of specific cell surface associated proteins or other proteins, needed for chondrogenic mesenchymal condensations. The role of TIP60 as a coactivator of Sox9 and L-Sox5 during chondrogenesis will be further characterized and new polypeptides that are part of transcriptional complexes, which interact with Sox9 will be identified. The patterns of Sox9 and L-Sox5 binding sites and those of polypeptide complexes, which interact with chondrocyte-specific promoters and enhancers, in intact chondrocytes will also be determined. In vitro reconstituted nucleosomal templates of the Col2a1 regulatory segments will be used in order to dissect the function of Sox9, L-Sox5 and other transcriptionally active polypeptides in chromatin disruption and transcription. These experiments should greatly enhance our understanding of the mechanisms whereby Sox9 controls chondrocyte differentiation and may suggest new therapeutic approaches for cartilage diseases.

描述（由申请人提供）：我们的长期目标是了解软骨细胞分化的转录机制。我们以前的工作已经证明，Sox 9在软骨形成中具有核心作用，并且在软骨细胞分化途径的多个步骤中是必需的。Sox 9最初需要建立骨软骨祖细胞;随后它是软骨形成间充质凝聚所需的。Sox 9是软骨细胞明显分化所需的，部分原因是Sox 9是表达Sox 5和Sox 6所需的，而Sox 5和Sox 6是明显软骨细胞分化所需的。后来在途径Sox 9仍然有另一个重要的作用，因为它参与生理抑制软骨细胞成熟为肥大软骨细胞。除了在软骨细胞分化途径中的作用外，Sox 9还需要用于少数其他细胞谱系的分化。提出了四个具体的目标，以获得新的见解的机制，Sox 9和L-Sox 5控制软骨细胞分化。首先将确定在软骨细胞分化程序的两个主要步骤中由Sox 9控制的基因库。还将测试Sox 9是否控制软骨形成间充质凝聚所需的特定细胞表面相关蛋白或其他蛋白的表达。TIP 60在软骨形成过程中作为Sox 9和L-Sox 5的共激活因子的作用将被进一步表征，并且将鉴定与Sox 9相互作用的转录复合物的一部分的新多肽。还将确定完整软骨细胞中Sox 9和L-Sox 5结合位点的模式以及与软骨细胞特异性启动子和增强子相互作用的多肽复合物的模式。将使用Col 2a 1调节区段的体外重构核小体模板，以剖析Sox 9、L-Sox 5和其他转录活性多肽在染色质破坏和转录中的功能。这些实验将大大提高我们对Sox 9控制软骨细胞分化的机制的理解，并可能为软骨疾病提供新的治疗方法。