The extracellular matrix (ECM) has a wide role in the development of the organism and elucidating the function of its components is critical to understanding morphogenesis. The current proposal will examine the role of fibrillins 1 and 2 in ECM function. Mutations in fibrillin-1 are associated with Marfan syndrome (MFS) while mutations in fibrillin-2 cause congenital contractual aracnodactyly (CCA). During the previous support cycle the Principal Investigator created a number of murine models of MFS and CCA by gene deletion and mutation of fibrillin genes. As a result, the hypothesis to be addressed is that fibrillin-microfibrils have superimposed functions in morphogenesis and homeostasis. The morphogenetic role in the skeleton of the mutant mice is documented by the overgrowth of fibrillin-1 deficient bones and the syndactyly of fibrillin-2 null limbs. In the current proposal, the Principal Investigator will extend these studies by creating additional murine fibrillin gene mutation models and then extensively examine the bone phenotype that is produced. This analysis will include categorization of the morphometric and biochemical properties of the fibrillin deficient bones, and the study of bone morphogenesis and growth in mutant organ cultures. Furthermore, studies are proposed to characterize the factors that control cartilage-specific fibrillin gene expression during development. This work is expected to enhance current understanding of the role of ECM in cartilage and bone development. Additional progress is expected from the interaction with other IPPG projects that study growth factors (Basilico and Rifkin) and chondrocyte determinants (Lufkin), as well as from relating findings in this application at the organ and organismal level through the Structure Function laboratory (Schaffler). Collectively, it is anticipated that this multidisciplinary IRPG will yield an integrated and comprehensive view of bone modeling and remodeling.
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