Transcriptional regulation of Sox9 in chondrogenesis

Sox9 在软骨形成中的转录调控

基本信息

批准号：
8546681
负责人：
Timothy Joseph Mead
金额：
$ 5.33万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-02-01 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8546681
关键词：
Adolescent Adult Affect American Binding Biochemical Cartilage Cartilage Diseases Cell Proliferation Cells Chondrocytes Chondrogenesis Chromosomal Rearrangement Clinical Commit Conserved Sequence Data Defect Degenerative polyarthritis Disease Elements Embryo Engineering Enhancers Ensure Epiphysial cartilage Extracellular Matrix Feedback Genes Genetic Transcription Goals Gonadal structure Grant Growth Human In Vitro Inherited Investigation Joints Knowledge Laboratories LacZ Genes Lead Maintenance Mediating Mesenchymal Molecular Mouse, Founder, Transgenic Mutant Strains Mice Neural Crest Pattern Primordium Procedures Regulation Regulator Genes Research Research Project Grants Rewards Skeleton Spinal Cord Staging Syndrome Testing Therapeutic Tissues Transact Transcriptional Regulation Transgenes Transgenic Mice activating transcription factor articular cartilage base campomelic dysplasia cartilage development cis acting element disease phenotype effective therapy enhancer binding protein experience gain of function improved in vivo loss of function malformation mouse genome novel novel therapeutics postnatal programs promoter repaired skeletal skeletal disorder skeletal dysplasia spatiotemporal therapeutic target transcription factor vertebrate genome

项目摘要

DESCRIPTION (provided by applicant): Inherited and acquired defects in the formation or adult maintenance of cartilage cause many types of skeletal dysplasias and joint degeneration diseases, namely osteoarthritis. Sox9 encodes a transcription factor that is absolutely required for cartilage formation. The mechanisms underlying Sox9 transcription in chondrocytes, however, remain largely unknown. Sox9 enhancers have been identified for developing gonad, neural crest, and spinal cord, but none have been discovered for chondrocytes. The overarching goal of the research project is to identify the mechanisms underlying Sox9 expression in chondrocytes. We have identified a highly conserved enhancer located far upstream of the Sox9 promoter. Preliminary results in transgenic mice indicate that this enhancer is active in proliferative chondrocytes in cartilage primordia and growth plates. I propose that this enhancer binds proteins that have a key role in ensuring Sox9 expression in these cells and are thereby required to maintain chondrocyte differentiation and ensure skeletal growth and timely ossification. The main goal of this project is to test this hypothesis by pursuing the following three specific aims: (1) define the domain of activity of the enhancer in vivo, (2) test whether th enhancer is required for Sox9 expression in vivo, and (3) identify the transcription factors that bind to and activate the Sox9 enhancer, and to determine their importance in chondrogenesis. Understanding the molecular basis of Sox9 expression in chondrogenesis will identify potential pharmacological therapeutic targets, which may have clinical implications for the treatment of skeletal dysplasias and degenerative cartilage diseases such as osteoarthritis.

描述（由申请人提供）：软骨形成或成人维持方面的遗传性和后天性缺陷导致多种类型的骨骼发育不良和关节退行性疾病，即骨关节炎。 Sox9 编码软骨形成所必需的转录因子。然而，软骨细胞中 Sox9 转录的机制仍然很大程度上未知。 Sox9 增强子已被鉴定用于性腺、神经嵴和脊髓的发育，但尚未发现软骨细胞的增强子。该研究项目的总体目标是确定软骨细胞中 Sox9 表达的机制。我们已经鉴定出位于 Sox9 启动子上游的高度保守的增强子。转基因小鼠的初步结果表明，该增强剂在软骨原基和生长板的增殖软骨细胞中具有活性。我认为这种增强子结合的蛋白质在确保这些细胞中 Sox9 表达方面发挥着关键作用，因此是维持软骨细胞分化、确保骨骼生长和及时骨化所必需的。该项目的主要目标是通过追求以下三个具体目标来检验这一假设：（1）定义增强子的体内活性域，（2）测试增强子是否是体内 Sox9 表达所必需的，以及（ 3) 鉴定结合并激活Sox9增强子的转录因子，并确定它们在软骨形成中的重要性。了解 Sox9 在软骨形成中表达的分子基础将确定潜在的药理学治疗靶点，这可能对骨骼发育不良和骨关节炎等退行性软骨疾病的治疗具有临床意义。