TGFbeta in the pathology and development of the spine

项目摘要。 这项研究的长期目标是了解参与发展和维持的信号， 轴向骨架，可以告知再生和工程策略。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活性的基因与脊柱病理学有关。它也被证明使用 Tgfbr 2是纤维组织发育和维持所必需的基因工程小鼠， 脊柱包括椎间盘的纤维环、韧带和肌腱。先前结果 在我的实验室获得的结果表明，Tgfb调节细胞命运的决定，在硬结，胚胎 脊椎中结缔组织的祖细胞。在本申请中，我们提出解决具有指导意义的 Tgfb调节脊柱纤维组织胚胎形成的机制。另外我们 我建议解决硬节再分割的问题，这是一个创造空间的胚胎过程。 脊柱中组织的组织结构。重新分段的改变预计将改变 细胞分化，影响许可信号和对指导信号作出反应的能力， 决定细胞命运最后，使用我实验室开发的小鼠模型， Tgfb如何在出生后纤维环中维持纤维特性的机制。整体 该建议的目的是：1）确定Tgfb用于产生纤维组织的信号通路， 2）绘制重新分段的过程，并确定 Tgfb介导的调节机制和3）了解Tgfb如何维持纤维环 出生后这里所描述的实验将提供有关发育的机理信息， 维护中轴骨架，并为未来的再生和工程策略提供基础 在脊椎上

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.