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

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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.