This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Extracellular matrix molecules play determining roles in development of complex structures such as the vertebrate eye and skeleton. Mutations in genes that encode proteins of the extracellular matrix demonstrate the importance of individual molecular constituents in the case of Stickler and Marshall syndromes in which a mutation in the Col11a1 acts to control cellular differentiation by interaction with regulartory signaling pathways. Alternatively, Col11a1 could act as a signaling molecule itself. Similarities exist between the phenotypes resulting from mutations in the BMP, Wnt, and PTHrP signaling pathways and mutations in Col11a1. The experimental approach proposed to address this hypothesis will combine three levels of analysis--a zebrafish model system for the analysis of vertebrate development, analysis of signaling pathways at the cellular level using cell culture, and molecular structure and interaction studies using biochemical and biophysical techniques to investigate molecular mechanisms of complex events during development and differentiation. The results of these studies will provide a more thorough understanding of the molecular and cellular mechanism of cell-matrix interactions and how such interactions influence signaling events. Moreover, we anticipate an increased understanding of how single molecules may be used for multiple purposes in a variety of contexts within a vertebrate organism, as well as the fundamental molecular events that are common to multiple unique outcomes during organogenesis. With an increase in understanding, we anticipate an improved ability to design new diagnostic approaches and therapeutic strategies to address the challenges introduced by mutations that affect eye and skeletal development.
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