The objective of this project is to understand the role of hyaluronan- cell interactions in limb vasculogenesis. Previous results suggest that such interactions modulate blood vessel formation, in that hyaluronan- endothelial cell interaction appears to be essential but high concentrations of hyaluronan, e.g. in the peripheral mesoderm of the embryonic limb, are inhibitory. A key factor in these events is a newly discovered hyaluronan-binding protein (HABP) that possesses the peptide motif, arg-gly-asp, that is recognized by several integrins. It is hypothesized that hyaluronan is bound to the surface of endothelial cells via a complex of this HABP and an integrin; it is further proposed that this interaction influences endothelial cell behavior, especially migration, which is an essential component of new vessel formation.
The specific aims of the project for this grant period are: 1. to produce full-length cDNAs for the HABP variants expressed by endothelial cells, and to use these cDNAs to obtain purified recombinant HABPs and to study their properties; 2. to isolate and characterize the integrin with which the HABP interacts, and to examine the role of interactions between this integrin, the HABP, and hyaluronan in endothelial cell attachment and migration; 3. to begin several approaches to further elucidation of the role of hyaluronan and HABPs in limb vasculogenesis. The results of these studies will lead to a better understanding of angiogenesis and vasculogenesis in limb development, and in other normal and disease processes. In addition this work will give new insights into the molecular mechanisms underlying cell migration and invasion, which are fundamental to tissue remodeling in development, healing and several diseases.
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