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开发和维护的信号 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。多态性和突变 调节 Tgfb 活性的基因与脊柱病理有关。它也被显示使用 基因工程小鼠中纤维组织的发育和维持需要Tgfbr2 脊柱包括椎间盘纤维环、韧带和肌腱。之前的结果 我的实验室获得的结果表明，Tgfb 调节骨片（胚胎细胞）中的细胞命运决定。 脊柱结缔组织的祖细胞。在本申请中，我们建议解决指导性问题 Tgfb 调节脊柱纤维组织胚胎形成的机制。此外，我们 提出解决骨片重新分割的问题，这是一个创造空间的胚胎过程 脊柱组织的组织。重新分割的改变预计会改变环境 哪些细胞分化，影响许可信号和响应指导信号的能力 控制细胞命运的决定。最后，使用我实验室开发的小鼠模型，我们将开始确定 Tgfb 如何发挥作用以维持出生后纤维环的纤维特征的机制。整体 该提案的目的是：1）确定 Tgfb 用于生成纤维组织的信号通路 胚胎发育期间的脊柱； 2) 绘制重新分割的过程并确定 Tgfb 介导的调节机制以及 3) 了解 Tgfb 如何维持纤维环 产后。这里描述的实验将提供有关发育和发育的机制信息 维护轴向骨架并为未来的再生和工程策略提供基础 在脊柱中。

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.