TGFbeta in the pathology and development of the spine

TGFbeta 在脊柱病理和发育中的作用

基本信息

批准号：
10731938
负责人：
Rosa A. Serra
金额：
$ 32.15万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-04 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10731938
关键词：
Address Affect Binding Proteins Biological Assay Biological Process Biology Cell Differentiation process Cells Cervical ChIP-seq Chick Embryo Competence Connective Tissue DNA Binding Data Degenerative Disorder Development Disease Dominant-Negative Mutation Drug Targeting Elements Embryo Embryonic Development Engineering Fibrocartilages Foundations Future Genes Genetic Polymorphism Genetically Engineered Mouse Genomics Growth Homeostasis Intervertebral disc structure Label Laboratories Ligaments Ligands Maintenance Maps Mediating Molecular Molecular Biology Motion Movement Mus Muscle Mutation Natural regeneration Nerve Pathology Pathway interactions Pattern Prevention Process Publishing Regulation Response Elements Role Sclerotome Signal Pathway Signal Transduction Signaling Protein Skeleton Somites Spinal Diseases Spinal Osteophytosis TGFB1 gene TGFB3 gene TGFBR2 gene Techniques Technology Tendon structure Testing Tissue Engineering Tissue imaging Tissues Transforming Growth Factor beta Transgenic Mice Vertebral column experimental study mRNA Expression member mouse model permissiveness posterior longitudinal ligament ossification postnatal progenitor receptor regenerative repaired scleraxis scoliosis skeletal skeletal tissue sternocostal joint transcription factor transcriptome sequencing

项目摘要

Project Summary. The long-term objective of this study is to understand signals involved in development and maintenance of the axial skeleton that can inform regenerative and engineering strategies. Members of the Tgfb superfamily are secreted signaling proteins that regulate many aspects of skeletal biology. Polymorphisms and mutations in genes that regulate Tgfb activity have been associated with pathology in the spine. It’s also been shown using genetically engineered mice that Tgfbr2 is required for development and maintenance of the fibrous tissues in the spine including the annulus fibrosus of the intervertebral disc, ligaments, and tendon. Previous results obtained in my laboratory indicate that Tgfb regulates cell fate decisions in the sclerotome, the embryonic progenitor of the connective tissues in the spine. In this application, we propose to address the instructive mechanisms whereby Tgfb regulates embryonic formation of fibrous tissues in the spine. In addition, we propose to address the problem of sclerotome resegmentation, an embryonic process that creates the spatial organization of tissues in the spine. Alterations in resegmentation would be expected to alter the context in which cells differentiate, affecting permissive signals and competence to respond to instructive signals that govern cell fate decisions. Finally, using a mouse model developed in my laboratory, we will start to determine the mechanisms of how Tgfb acts to maintain fibrous character in the postnatal annulus fibrosus. The overall aims of this proposal are to: 1) Determine the signaling pathways used by Tgfb to generate fibrous tissues of the spine during embryonic development; 2) To map the process of resegmentation and determine the mechanism of Tgfb-mediated regulation and 3) To understand how Tgfb maintains annulus fibrosus postnatally. The experiments described here will provide mechanistic information about development and maintenance of the axial skeleton and provide a foundation for future regeneration and engineering strategies in the spine.

项目摘要。这项研究的长期目标是了解参与开发和维护的信号可以为再生和工程策略提供信息的轴向骨骼。 TGFB超家族的成员是调节骨骼生物学许多方面的分泌信号蛋白。多态性和突变调节TGFB活性的基因与脊柱中的病理有关。也显示了一般设计的小鼠TGFBR2是开发和维护纤维计时所必需的脊柱包括椎间盘，韧带和肌腱的纤维纤维。先前的结果在我的实验室中获得的表明TGFB调节了胚胎中的细胞命运决定脊柱连接时机的祖细胞。在此应用程序中，我们建议解决启发性 TGFB调节脊柱中纤维组织的胚胎形成的机制。另外，我们解决硬化症关系问题的提议，这是一个胚胎过程，可以创建空间脊柱中组织的组织。期望关系改变将改变哪些细胞分化，影响允许的信号和能力，以响应具有指示性信号控制细胞脂肪决策。最后，使用在我的实验室中开发的鼠标模型，我们将开始确定 TGFB如何在产后纤维纤维中保持纤维性特征的机制。总体该建议的目的是：1）确定TGFB用于生成纤维组织的信号通路胚胎发育过程中的脊柱； 2）映射关系的过程并确定 TGFB介导的调节机制和3）了解TGFB如何维持环形纤维产后。此处描述的实验将提供有关开发和的机械信息维护轴向骨骼并为将来的再生和工程策略奠定了基础在脊柱中。