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育和维护的信号 可以为再生和工程策略提供信息的轴向骨架。TGFb超级家族的成员是 分泌的信号蛋白，调节骨骼生物学的许多方面。基因的多态和突变 调节TGFb活性的基因与脊柱的病理有关。它也被用来展示 TGFBR2基因工程小鼠在体内纤维组织的发育和维持中是必需的 包括间盘的纤维环、韧带和肌腱的脊柱。之前的结果 在我的实验室获得的结果表明，TGFb调节着核盘体中的细胞命运决定，即胚胎 脊椎中结缔组织的祖先。在本应用程序中，我们建议解决具有启发性的 TGFb调节脊柱纤维组织胚胎形成的机制。此外，我们 建议解决菌核体再分割的问题，这是一个创造空间的萌芽过程 脊椎组织脊椎组织的组织重新分割的变化预计将改变 哪些细胞分化，影响许可信号和对指示信号做出反应的能力 管理细胞命运的决定。最后，使用我实验室开发的老鼠模型，我们将开始确定 TGFb在生后纤维环中维持纤维特性的作用机制。整体而言 这项建议的目的是：1)确定TGFb用来产生纤维组织的信号通路 胚胎发育过程中的脊柱；2)绘制重新分段的过程图，并确定 TGFb介导的调节机制及3)理解TGFb如何维持纤维环 出生后。这里描述的实验将提供有关开发和开发的机械信息 维护轴向骨架，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.