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。我们以前的工作表明，Sox9在软骨生成中具有核心作用，并且需要在软骨细胞分化途径的多个步骤中。最初需要Sox9建立骨软骨蛋白酶；随后，这是软骨间充质凝结所必需的。然后需要SOX9才能明显地分化软骨细胞，部分原因是Sox9表达Sox5和Sox6需要，这是明显的软骨细胞分化所需的。后来，在途径中，Sox9仍然具有另一个重要作用，因为它参与了软骨细胞成熟到肥厚的软骨细胞中的生理抑制作用。除了其在软骨细胞分化途径中的作用外，还需要Sox9来分化少数其他细胞谱系。提出了四个特定的目标，以获得SOX9和L-SOX5控制软骨细胞分化的机制的新见解。首先要确定由Sox9控制的基因库，该基因在软骨细胞分化程序的两个主要步骤中。该假设还将测试SOX9是否控制着软骨间充质凝结所需的特定细胞表面相关蛋白或其他蛋白的表达。 TIP60作为软骨发生过程中SOX9和L-SOX5的共激活因子的作用将进一步表征，并且将鉴定出与SOX9相互作用的新多肽。在完整的软骨细胞中，SOX9和L-SOX5结合位点与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也将得到确定。为了剖析SOX9，L-SOX5和其他转录活性多肽在染色质破坏和转录中，将使用COL2A1调节片段的体外重构核小体模板。这些实验应大大增强我们对SOX9控制软骨细胞分化的机制的理解，并可能提出针对软骨疾病的新治疗方法。