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Design of bone morphogenetic protein 2/nodal chimeras


The TGF-[beta] superfamily is comprised of over thirty ligands responsible for numerous cellular processes including early embryonic development, tissue patterning and homeostasis, bone formation, wound healing and fibrosis. Research is directed at utilizing these ligands as protein-based therapies. Bone Morphogenetic Protein 2 (BMP-2) is currently used to facilitate fracture repair and spinal fusions. In order to sustain these efforts, E. Coli derived, chemically refolded ligands provide an efficient, cost effective alternative to using stably transfected cell lines. Currently, less than a dozen of the TGF-[beta] ligands have been successfully refolded. The aim of my project was to create chimeric proteins by recombining a ligand that refolds well with a non- refolding ligand. Nodal, an essential TGF-[beta] ligand responsible for axis formation in early embryonic development, was recombined with BMP-2, a ligand known for its efficient refolding. Using our strategy, we successfully generated multiple ligands with Cripto- dependent signaling comparable to wild type Nodal. Based on our findings, we were able to identify a region within Nodal's structure that is critical for Cripto-dependent signaling. We will use our chimeras to better understand receptor ligand compelx formation and its modulation of intracellular downstream signaling

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