CONTROL OF CHONDROCYTE DIFFERENTIATION

软骨细胞分化的控制

• 批准号: 7656869
• 负责人: Benoit de Crombrugghe
• 金额: $ 40.26万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-20 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7656869
• 关键词: Binding Sites; Biochemical; Biochemical Genetics; Cartilage Diseases; Cell Lineage; Cell surface; Cells; Cephalic; Chondrocytes; Chondrogenesis; Chromatin; Complex; DNA; Enhancers; Gene Targeting; Genes; Genetic; Genetic Transcription; Genomics; Goals; Gonadal structure; HTATIP gene; Heart Septum; In Vitro; Laboratories; Mesenchymal; Neural Crest Cell; Neuraxis; Neuroglia; Paneth Cells; Pathway interactions; Pattern; Physical condensation; Physiological; Proteins; Role; Signaling Molecule; Specificity; Testing; Therapeutic; Work; insight; intestinal epithelium; male; novel therapeutic intervention; polypeptide; programs; promoter; reconstitution; research study; sertoli cell; transcription factor

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。我们之前的工作已经证明 Sox9 在软骨形成中起着核心作用，并且在软骨细胞分化途径的多个步骤中都是必需的。 Sox9 最初是建立骨软骨祖细胞所必需的；随后它是软骨形成间充质凝结所必需的。 Sox9 是软骨细胞显性分化所必需的，部分原因是 Sox9 是 Sox5 和 Sox6 表达所必需的，而 Sox5 和 Sox6 是显性软骨细胞分化所必需的。随后，在该途径中，Sox9 仍然具有另一个重要作用，因为它参与软骨细胞成熟为肥大软骨细胞的生理抑制。除了在软骨细胞分化途径中发挥作用外，Sox9 也是少数其他细胞谱系分化所必需的。提出了四个具体目标，以获得对 Sox9 和 L-Sox5 控制软骨细胞分化机制的新见解。首先将确定软骨细胞分化程序中两个主要步骤中由 Sox9 控制的基因库。该假设还将检验 Sox9 是否控制软骨形成间充质浓缩所需的特定细胞表面相关蛋白或其他蛋白的表达。 TIP60 作为 Sox9 和 L-Sox5 在软骨形成过程中的共激活剂的作用将得到进一步表征，并且将鉴定作为转录复合物一部分的与 Sox9 相互作用的新多肽。还将确定完整软骨细胞中 Sox9 和 L-Sox5 结合位点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。 Col2a1 调节片段的体外重构核小体模板将用于剖析 Sox9、L-Sox5 和其他转录活性多肽在染色质破坏和转录中的功能。这些实验将极大地增强我们对 Sox9 控制软骨细胞分化机制的理解，并可能为软骨疾病的新治疗方法提供建议。