The central theme of this proposal is the cellular and molecular events that lead to differentiation of most of the major tissues of the developing limb, namely cartilage, bone, tendon, muscle, and the vasculature. Project I will examine the role of a putative complex of hyaluronan, hyaluronan-binding protein and an integrin in regulating endothelial cell behavior, and the molecular nature of the protein components of this complex. Project II will continue to elucidate the specific regulatory components involved in cartilage hypertrophy, especially type X collagen, proteoglycans and other genes specifically expressed during hypertrophy. Project III will study the regulation of a critical step in maturation of collagen fibers during tendon development, also focussing on proteoglycan-collagen interactions and expression of genes at the time of tendon maturation. Project IV will further study translation-inhibitory RNAs in the regulation of muscle growth, and will also apply this concept to early differentiation events in the limb. The individual projects will employ a large variety of technical approaches to achieve their aims; a major integrating factor in the program is the sharing of the broad range of skills that have been mastered by the members of the program in order to facilitate progress in each project and to stimulate new experimental approaches. These studies will lead to a better understanding of morphogenesis and differentiation during limb development, and will provide a more informed basis for investigations of genetic and teratologically produced limb anomalies.
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