Establishing a Link between Astacin Proteases. TGF-Beta Signaling and the Extracellular Matrix. A major theme has evolved from our understanding of diverse biological systems. Namely, that the conservation of molecules among species as disparate as fruit flies and humans allows us to evaluate signaling pathways in one with the strong possibility that similar regulatory mechanisms are common to both. This has in fact been the case for factors in a highly complex and strictly conserved BMP signaling pathway. Members of the astacin family of metalloproteases are proposed to act in this pathway by directly targeting molecules that antagonize BMP signaling and therefore represent a pivotal level of regulation. Our work is designed to understand the role of the astacin protease SpAN from the sea urchin, Strongylocentrotus purpuratus, (1) in normal development and (II) In regulating BMP signaling in other developmental systems. I) While the pattern and regulation of SpAN gene expression has been studied extensively, the developmental expression and biochemical activity of the SpAN protease has not been characterized. I have developed a polyclonal antisera generated against SpAN and localized expression of the protease to the apical side of developing blastulae. In order to understand SpAN's role in morphogenesis, we propose methods to disrupt SpAN activity in vivo and to isolate possible biochemical target(s). II) Related astacin proteases. Including a large family of Tolloid molecules from vertebrates and Drosophila, play an important role in pattern formation and are thought to act by enhancing BMP signaling. We provide a biochemical explanation for SpAN activity in this pathway as the BMP antagonist Chordin is cleaved by SpAN in an in vitro assay. In addition to their role in early development, BMPs are potent osteo-genic agents. We will test, directly, SpAN's ability to modulate bone growth in a rat mandible defect model. Key Words: Astacin protease, TGF Beta-Bone morphogenetic protein, Signaling, extracellular matrix, sea urchin
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