TGF-Beta in the Pathology and Development of the Spine

TGF-β 在脊柱病理学和发育中的作用

• 批准号: 7798113
• 负责人: Rosa A. Serra
• 金额: $ 30.25万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-18 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7798113
• 关键词: Accounting; Address; Adenoviruses; Adult; Affect; Ankylosing spondylitis; Anterior; Apoptosis; Biological Assay; Bromodeoxyuridine; Cells; Congenital Abnormality; Custom; Defect; Development; Disease; Dominant-Negative Mutation; Dorsal; Elements; Embryonic Development; Failure; Genes; Genetic Polymorphism; Growth; Homeostasis; Human; In Situ Hybridization; In Situ Nick-End Labeling; Intervertebral disc structure; Joints; Kyphosis deformity of spine; LacZ Genes; Lateral; Left; Ligaments; Maintenance; Measures; Mediating; Mesenchymal; Modeling; Molecular; Mus; Mutation; Natural regeneration; Pathology; Pathway interactions; Pattern; Phenotype; Preparation; Primary Cell Cultures; Process; Reporter; Research Personnel; Role; Sclerotome; Signal Transduction; Signaling Protein; Skeleton; Spinal Osteophytosis; Spondylarthropathies; Staining method; Stains; Structure; Testing; Time; Tissues; Transforming Growth Factor beta; Transgenic Mice; Vertebral column; base; cell motility; cohort; fibromodulin; in vivo Model; insight; malformation; member; migration; nucleus pulposus; programs; promoter; receptor; repaired; skeletal; skeletal disorder; skeletal tissue; spine bone structure; versican

DESCRIPTION (provided by applicant): The long-term objective of this study is to provide insight into mechanisms of pathology in the spine through an understanding of signals involved in the formation of the axial skeleton as well as in the maintenance of tissue structure and function in the adult. We propose that signaling through Tgfbr2 regulates both the development of the axial skeleton and the maintenance of tissues in the adult spine. Members of the TGF-b superfamily are secreted signaling proteins that regulate many aspects of development and tissue homeostasis including growth, patterning, and cellular differentiation. Polymorphisms and mutations in human Tgfb genes have been associated with pathology in the adult spine. Previously, we generated transgenic mice that express a dominant-negative mutation of the TGF-B Type II receptor in post-natal skeletal tissue. The mice demonstrated a progressive skeletal disease with pathology resembling that observed in human spondyloarthropathies. We also recently showed that deletion of the TGF-b type II receptor in Col2a expressing tissue results in alterations in the development of the axial skeleton including failures in the formation of the vertebrae and intervertebral discs. The results together suggest TGF-b has an important role in regulating both embryonic development of the axial skeleton and tissue homeostasis in the adult spine, however, the mechanistic basis of TGF-b action in the axial skeleton is not known. We propose to address this issue using genetically altered mouse and primary cell culture models. We will test the following specific hypotheses: 1) Signaling through Tgfbr2 mediates development of the vertebrae by regulating the expansion of the sclerotome. 2) Signaling through Tgfbr2 mediates the development of dorsal vertebral structures by regulating dorsal migration of sclerotomal cells. 3) Tgfbr2 regulates the patterning of the sclerotome. 4A) Tgfbr2 directs differentiation of sclerotomal cells towards the annulus fibrosus phenotype. 4B) TGF-b regulates the formation and maintenance of the IVD by antagonizing BMP activity. Understanding how specific cellular differentiation pathways occur in the first place and how differentiation is maintained in the adult will provide a basis for repair and regeneration strategies in the spine.

描述（由申请人提供）：本研究的长期目标是通过了解参与中轴骨骼形成以及组织结构和功能维持的信号来深入了解脊柱病理机制在成人中。我们认为，通过 Tgfbr2 的信号传导可调节成人脊柱中轴骨骼的发育和组织的维护。 TGF-b 超家族的成员是分泌性信号蛋白，可调节发育和组织稳态的许多方面，包括生长、模式形成和细胞分化。人类 Tgfb 基因的多态性和突变与成人脊柱的病理有关。此前，我们培育了在出生后骨骼组织中表达 TGF-B II 型受体显性失活突变的转基因小鼠。这些小鼠表现出进行性骨骼疾病，其病理学类似于在人类脊柱关节病中观察到的病理学。我们最近还发现，表达 Col2a 的组织中 TGF-b II 型受体的缺失会导致中轴骨骼发育的改变，包括椎骨和椎间盘形成的失败。这些结果共同表明，TGF-b 在调节中轴骨骼的胚胎发育和成人脊柱的组织稳态中具有重要作用，然而，TGF-b 在中轴骨骼中作用的机制基础尚不清楚。我们建议使用基因改造的小鼠和原代细胞培养模型来解决这个问题。我们将测试以下具体假设：1) Tgfbr2 信号传导通过调节骨节的扩张来介导椎骨的发育。 2) Tgfbr2 信号传导通过调节巩膜细胞的背侧迁移来介导背侧椎骨结构的发育。 3) Tgfbr2 调节骨节的模式。 4A) Tgfbr2 引导巩膜细胞向纤维环表型分化。 4B) TGF-b 通过拮抗 BMP 活性来调节 IVD 的形成和维持。了解特定细胞分化途径最初是如何发生的以及成人中如何维持分化将为脊柱修复和再生策略提供基础。