TGF-Beta in the Pathology and Development of 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维持成人组织结构和功能的信号，深入了解脊柱病理机制。我们建议，信号通过Tgfbr 2调节轴向骨架的发展和维护组织在成人脊柱。TGF-β超家族成员是分泌的信号蛋白，其调节发育和组织稳态的许多方面，包括生长、图案化和细胞分化。人类Tgfb基因的多态性和突变与成人脊柱的病理学相关。以前，我们产生了转基因小鼠，表达显性负突变的TGF-β II型受体在出生后的骨骼组织。小鼠表现出进行性骨骼疾病，其病理学与在人类脊柱关节病中观察到的相似。我们最近还表明，在表达Col 2a的组织中TGF-b II型受体的缺失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-β在调节胚胎中轴骨骼发育和成年脊柱组织稳态方面具有重要作用，然而，TGF-β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变的小鼠和原代细胞培养模型来解决这个问题。我们将测试以下特定假设：1）通过Tgfbr 2的信号传导通过调节硬骨节的扩张介导椎骨的发育。2)通过Tgfbr 2的信号传导通过调节巩膜瘤细胞的背侧迁移来介导背侧脊椎结构的发育。3)tgfbr 2调节硬节的图案化。4A）Tgfbr 2指导硬化瘤细胞向纤维环表型分化。4 B）TGF-β通过拮抗BMP活性调节IVD的形成和维持。了解特定的细胞分化途径是如何发生的，以及分化是如何在成人中维持的，将为脊柱的修复和再生策略提供基础。

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.