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

描述（由申请人提供）：发育生物学是研究具有专门功能的细胞如何从未分化的细胞中衍生出来，以及细胞如何相互作用并与环境相互作用，最终形成组织和器官。TGF-？超家族是调节发育和组织稳态许多方面的分泌信号蛋白，包括生长、图案化和细胞分化。调节Tgfb活性的基因的多态性和突变与成人脊柱的病理学有关。以前，我们使用基因工程小鼠模型表明，Tgfbr 2是椎间盘（IVD）发育和维持所必需的。在上一个资助期发表的结果表明，Tgfb 1）抑制椎骨软骨的形成以维持IVD边界，2）促进纤维环与硬化体的分化。本研究的长期目标是了解正常参与IVD发育的信号，以便将模拟正常发育的体外过程应用于组织工程策略。基于已发表的结果和上一个资助期获得的初步数据的特定假设将在以下特定目标中进行测试：#1测试转录因子Erg和c-Maf在Tgfb介导的IVD发展调控中的作用。#2鉴定IVD分化的正性转录因子调节因子。#3为了测试Tgfb足以诱导在PCL/Coll混合支架上生长的未分化间充质细胞中的细胞排列和层状结构的假设。这里描述的实验将描述IVD开发的最早阶段，并为未来开发IVD工程提供必要的信息。

DESCRIPTION (provided by applicant): Developmental biology is the study of how cells with specialized functions are derived from undifferentiated cells and how cells interact with each other and their environment to ultimately form tissues and organs. Members of the TGF-? superfamily are secreted signaling proteins that regulate many aspects of development and tissue homeostasis including growth, patterning, and cellular differentiation. Polymorphisms and mutations in genes that regulate Tgfb activity have been associated with pathology in the adult spine. Previously, we showed using genetically engineered mouse models that Tgfbr2 is required for development and maintenance of the intervertebral disc (IVD). Results published during the previous funding period suggest that Tgfb 1) inhibits the formation of vertebral cartilage to maintain the IVD boundary and 2) promotes differentiation of annulus fibrosus from sclerotome. The long-term objective of this study is to understand signals normally involved in IVD development so that in vitro processes that mimic normal development can be applied to tissue engineering strategies. Specific hypotheses based on published results and preliminary data obtained during the previous funding period will be tested in the following specific aims: #1 To test the roles of the transcription factors Erg and c-Maf in Tgfb-mediated regulation of IVD development. #2 To identify positive transcription factor regulators of IVD differentiation. #3 To test the hypothesis that Tgfb is sufficient to induce cell alignment and lamellar structure in undifferentiated mesenchymal cells grown on a PCL/Col1 blended scaffold. The experiments described here will characterize the earliest stages of IVD development and provide information necessary for future efforts to developmentally engineer IVD.