CONTROL OF CHONDROCYTE DIFFERENTIATION

软骨细胞分化的控制

• 批准号: 7468048
• 负责人: Benoit de Crombrugghe
• 金额: $ 39.31万
• 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/7468048
• 关键词: Binding Sites; Biochemical; Biochemical Genetics; Cartilage Diseases; Cell Lineage; Cell surface; Cells; Cephalic; Chondrocytes; Chondrogenesis; Chromatin; Complex; DNA; Disruption; Enhancers; Gene Targeting; Genes; Genetic; Genetic Transcription; Genomics; Goals; Gonadal structure; HTATIP gene; Heart Septum; In Vitro; Laboratories; Mesenchymal; Neural Crest Cell; Neuraxis; Neuroglia; Numbers; Paneth Cells; Pathway interactions; Pattern; Physical condensation; Physiological; Proteins; Role; Signaling Molecule; Specificity; Testing; Therapeutic; Work; human HTATIP protein; insight; intestinal epithelium; male; novel therapeutics; 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(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，Sox9在软骨形成中起核心作用，在软骨细胞分化的多个步骤中都需要Sox9。SOX9最初是建立骨软骨前体细胞所必需的；随后，软骨源性间充质凝聚也需要SOX9。因此，软骨细胞的明显分化需要Sox9，部分原因是Sox5和Sox6的表达需要Sox9，而Sox5和Sox6是软骨细胞明显分化所必需的。在后来的途径中，Sox9仍然发挥着另一个重要作用，因为它参与了生理上抑制软骨细胞向肥大软骨细胞成熟的过程。Sox9除了在软骨细胞分化途径中发挥作用外，还需要用于少数其他细胞系的分化。本文针对Sox9和L-Sox5调控软骨细胞分化的机制提出了四个具体的研究目标。将首先确定在软骨细胞分化程序的两个主要步骤中由Sox9控制的基因谱系。这一假说还将检验Sox9是否控制特定细胞表面相关蛋白质或其他蛋白质的表达，这些蛋白质是软骨源性间充质凝聚所需的。Tip60作为Sox9和L-Sox5在软骨形成过程中的共激活因子的作用将得到进一步的表征，并将发现与Sox9相互作用的转录复合体中的新多肽。还将确定完整软骨细胞中Sox9和L-Sox5结合位点的模式以及与软骨细胞特异性启动子和增强剂相互作用的多肽复合体的模式。体外重组的COL2a1调控片段的核小体模板将被用来剖析Sox9、L-Sox5和其他转录活性多肽在染色质干扰和转录中的功能。这些实验将极大地提高我们对Sox9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。