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特殊功能的细胞如何从未分化的细胞中衍生出来，以及细胞如何与彼此及其环境相互作用，最终形成组织和器官。TGF-？超家族是分泌的信号蛋白，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。调节Tgfb活性的基因的多态性和突变与成人脊柱的病理有关。先前，我们使用基因工程小鼠模型证明Tgfbr2是椎间盘（IVD）发育和维持所必需的。在之前的资助期内发表的结果表明，Tgfb 1)抑制椎软骨的形成以维持IVD边界，2)促进纤维环从硬核组分化。本研究的长期目标是了解IVD发育过程中通常涉及的信号，以便模拟正常发育的体外过程可以应用于组织工程策略。基于已发表的结果和先前资助期间获得的初步数据的特定假设将在以下具体目标中进行测试：1 .测试转录因子Erg和c-Maf在tgfb介导的IVD发展调节中的作用。#2确定IVD分化的阳性转录因子调节因子。为了验证Tgfb足以诱导PCL/Col1混合支架上生长的未分化间充质细胞排列和片层结构的假设。这里描述的实验将描述IVD发展的早期阶段，并为未来发展工程IVD的努力提供必要的信息。

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.