Transcriptional control of growth plate chondrocytes

生长板软骨细胞的转录控制

• 批准号: 10620128
• 负责人: VERONIQUE M LEFEBVRE
• 金额: $ 58.81万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-15 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10620128
• 关键词: 3-Dimensional; Adolescent; Affect; Automobile Driving; Binding; Biological Assay; Cartilage; Cells; Chondrocytes; Chondrogenic Neoplasm; Chromatin; Complex; DNA Binding; Data; Degenerative polyarthritis; Disease; Enhancers; Ensure; Epiphysial cartilage; FGFR3 gene; Fetus; Genes; Genetic; Genetic Recombination; Genome; Genomics; Growth; Heterozygote; Individual; Knockout Mice; Limb Bud; Maintenance; Molecular; Mus; Newborn Infant; Osteoblasts; Pathology; Physiologic Ossification; Process; Proteins; RUNX3 gene; Role; SOX5 gene; SOX6 gene; Solid; Structure; Tertiary Protein Structure; Testing; Tissues; Transcriptional Regulation; chondrodysplasia; cofactor; fetal; human disease; in vivo; innovation; insight; joint destruction; malformation; mutant; novel; postnatal development; premature; prevent; programs; promoter; psychosocial; recruit; runx proteins; skeletal; skeletal dysplasia; skeletogenesis; synergism; transcription factor; transcriptome; tumor; whole genome

PROJECT SUMMARY Growth plates are highly specialized cartilage structures that ensure skeletal growth and endochondral ossification during fetal and postnatal development. They are formed and maintained by chondrocytes, as these cells follow a spatially and temporally tightly controlled multi-step differentiation program. The present project focuses on transcription factors that have pivotal roles in effecting this program, but whose modes of actions remain incompletely deciphered. It will test the paradigm-shifting hypothesis that SOX9, its cofactors SOX5 and SOX6, and RUNX2 and RUNX3 fulfill many of their main functions in a cooperative manner. This hypothesis is based on a solid scientific premise that includes co-expression of the factors in growth plate chondrocytes, the presence of RUNT-domain motifs in many chondrocyte-specific enhancers bound by SOX9, and preliminary evidence that the SOX and RUNX proteins have synergistic activities in enhancer activation. Specific Aim 1 is to determine whether SOX5/6, SOX9 and RUNX2/3 genetically interact during growth plate formation in mouse fetuses and in the maintenance of active growth plates in juvenile mice. Specific Aim 2 is to profile the whole genetic targetomes of SOX5/6, SOX9 and RUNX2/3 in growth plate chondrocytes, and to assess and validate their overlap. Specific Aim 3 is to identify mechanisms underlying SOX5/6, SOX9 and RUNX2/3 cooperativity. The proteins will be tested for roles in inducing chromatin accessibility and three- dimensional connectivity, and for cooperativity in DNA binding and recruitment of functional partners. New findings should have a significant impact on current understanding of fundamental mechanisms governing the formation and maintenance of growth plates and other cartilage types. They should thereby help uncover the molecular basis of many types of pathologies, including chondrodysplasias, tumors and joint degenerative diseases, and also suggest novel, innovative and efficient treatments for these still unsatisfactorily treatable diseases.

项目概要 生长板是高度专业化的软骨结构，可确保骨骼生长和软骨内生长 胎儿和产后发育期间的骨化。它们由软骨细胞形成和维持，如 这些细胞遵循空间和时间上严格控制的多步分化程序。现在的 该项目重点关注在影响该程序中发挥关键作用的转录因子，但其作用模式 行动仍未完全破译。它将检验 SOX9 及其辅助因子的范式转换假设 SOX5和SOX6以及RUNX2和RUNX3以协作方式履行其许多主要功能。这 假设基于坚实的科学前提，其中包括生长板中因子的共表达 软骨细胞，许多与 SOX9 结合的软骨细胞特异性增强子中存在 RUNT 结构域基序， 初步证据表明 SOX 和 RUNX 蛋白在增强子激活中具有协同活性。 具体目标 1 是确定 SOX5/6、SOX9 和 RUNX2/3 在生长板过程中是否存在遗传相互作用 小鼠胎儿的形成和幼年小鼠活跃生长板的维持。具体目标 2 是 分析生长板软骨细胞中 SOX5/6、SOX9 和 RUNX2/3 的整个遗传靶标组，并 评估并验证它们的重叠。具体目标 3 是确定 SOX5/6、SOX9 和 SOX5/6 的潜在机制 RUNX2/3 协作性。将测试这些蛋白质在诱导染色质可及性和三- 维度连接性，以及 DNA 结合和功能伙伴招募方面的协作性。新的 调查结果应对当前对基本机制的理解产生重大影响 生长板和其他软骨类型的形成和维护。因此，他们应该帮助揭露 许多类型病理学的分子基础，包括软骨发育不良、肿瘤和关节退行性变 疾病，并对这些仍不能令人满意地治疗的疾病提出新颖、创新和有效的治疗方法 疾病。