TGF-beta in the pathology and development of the spine.

描述(申请人提供)：这项研究的长期目标是通过了解与中轴骨的形成以及成人的组织结构和功能的维持有关的信号来洞察脊柱的病理机制。我们认为，通过TGFBR2的信号既调节了中轴骨骼的发育，也调节了成年脊柱组织的维持。转化生长因子-b超家族的成员是分泌的信号蛋白，调节发育和组织动态平衡的许多方面，包括生长、模式和细胞分化。人类TGFb基因的多态和突变与成人脊柱的病理有关。此前，我们培育的转基因小鼠在出生后骨骼组织中表达了转化生长因子-βII型受体的显性负突变。这些小鼠表现出一种进行性骨骼疾病，其病理与人类脊柱关节病相似。我们最近还发现，在表达COL2a的组织中，转化生长因子-βII型受体的缺失会导致中轴骨发育的改变，包括椎骨和椎间盘的形成失败。这些结果提示，转化生长因子-β对成人脊柱中轴骨的胚胎发育和组织内稳态具有重要的调节作用，但其作用的机制尚不清楚。我们建议使用转基因小鼠和原代细胞培养模型来解决这个问题。我们将检验以下特定的假设：1)通过TGFBR2的信号通过调节硬化症的扩张来调节椎骨的发育。2)TGFBR2信号通过调节脊椎背侧细胞的迁移来调节脊椎背侧结构的发育。3)TGFBR2调控核盘菌的构型。4A)TGFBR2引导硬结细胞向纤维环表型分化。4B)转化生长因子-β通过拮抗BMP活性调节IVD的形成和维持。首先了解特定的细胞分化途径是如何发生的，以及成人是如何保持分化的，这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.