Transcriptional control of growth plate chondrocytes

生长板软骨细胞的转录控制

基本信息

批准号：
10342008
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
项目类别：
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/10342008
关键词：
3-Dimensional Adolescent Affect Automobile Driving Binding Biological Assay Cartilage Cells Chondrocytes Chondrogenic Neoplasm Chromatin Complex DNA Binding Data Degenerative Disorder Disease Enhancers Ensure Epiphysial cartilage FGFR3 gene Fetal Development Fetus Genes Genetic Genetic Recombination Genome Genomics Growth Individual Joints 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 base chondrodysplasia cofactor 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 transcription factor transcriptome tumor whole genome

3-Dimensional Adolescent Affect Automobile Driving Binding Biological Assay Cartilage Cells Chondrocytes Chondrogenic Neoplasm Chromatin Complex DNA Binding Data Degenerative Disorder Disease Enhancers Ensure Epiphysial cartilage FGFR3 gene Fetal Development Fetus Genes Genetic Genetic Recombination Genome Genomics Growth Individual Joints 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 base chondrodysplasia cofactor 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 transcription factor transcriptome tumor whole genome

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项目摘要

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.

项目摘要生长板是高度专业的软骨结构，可确保骨骼生长和内侧软骨胎儿和产后发育过程中的骨化。它们由软骨细胞形成和维护这些单元遵循空间和时间紧密控制的多步分化程序。现在项目着重于在影响该程序中具有关键作用的转录因素，但其模式行动仍然不完全解密。它将测试其辅助因子Sox9的范式转移假设 Sox5和Sox6，Runx2和Runx3以合作的方式履行了许多主要功能。这假设基于一个稳定的科学前提，其中包括生长板中因子的共表达软骨细胞，在许多软骨细胞特异性增强子中的runt域基序的存在，以及初步证据表明，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在生长板期间是否在遗传上相互作用小鼠胎儿的形成和少年小鼠的活性生长板的维持。具体目标2是在生长板软骨细胞中介绍Sox5/6，Sox9和Runx2/3的整个遗传靶点，以及评估并验证其重叠。特定目的3是确定Sox5/6，Sox9和 Runx2/3合作。将测试蛋白质在诱导染色质访问性和三蛋白质中的作用维度连通性，以及功能伙伴的DNA结合和募集的合作。新的调查结果应对当前对管理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，他们应该帮助发现许多类型的病理的分子基础，包括软骨发育不全，肿瘤和关节退化疾病，还为这些疾病提出了新颖，创新和有效的治疗方法疾病。