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理解涉及成人轴骨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。我们认为，通过Tgfbr2发出的信号调节成人脊柱中轴骨骼的发育和组织的维持。TGF-b超家族的成员是分泌的信号蛋白，调节发育和组织稳态的许多方面，包括生长，模式和细胞分化。人类Tgfb基因的多态性和突变与成人脊柱的病理有关。在此之前，我们培育了在出生后骨骼组织中表达TGF-B型II受体显性阴性突变的转基因小鼠。小鼠表现出一种进行性骨骼疾病，其病理类似于在人类脊椎关节病中观察到的。我们最近还发现，Col2a表达组织中TGF-b II型受体的缺失会导致轴向骨骼发育的改变，包括椎骨和椎间盘形成的失败。综上所述，TGF-b在调节成人脊柱轴骨的胚胎发育和组织稳态中起着重要作用，然而，TGF-b在轴骨中的作用机制尚不清楚。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。我们将验证以下具体假设：1)通过Tgfbr2的信号传导通过调节硬核组的扩张来介导椎骨的发育。2) Tgfbr2信号通路通过调节硬化层细胞的背侧迁移介导脊柱背侧结构的发育。3) Tgfbr2调节硬膜组的模式。4A) Tgfbr2引导硬化细胞向纤维环表型分化。4B) TGF-b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，以及如何在成人中维持分化，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.