Laminins are major components of the extracellular matrix and influence a variety of important biological processes including cell attachment, migration, angiogenesis, and wound healing and tissue development. The biomedical importance of laminins is best illustrated by human severe blistering disease, epidermolysis bullosa, due to the deficiency of laminin 5 and subsequent failure of wound repair. It has been recently found that two newly identified laminins, 8 (alpha4beta1gamma1) and 10 (alpha5beta1gamma1), are the major laminins produced by human dermal-microvascular endothelial cells (HDMECs). They likely play important roles in endothelial cell attachment, spreading and angiogenesis. Our long-range goal is to improve the therapeutic outcomes of wound healing. The objective of this application is to determine the roles of the Iaminins 8 and 10 in wound angiogenesis. In this study, I propose two specific aims: 1. To determine the functions of laminin 8 and laminin 10 in endothelial cell attachment and migration. Cell attachment and migration are two essential and tightly linked processes in wound angiogenesis. The ability of these two molecules to promote cell attachment and migration of HDMECs and the cell surface receptors responsible for these interactions will be determined using methods of cell binding and migration assays in vitro. 2. To determine the roles of laminins 8 and 10 in endothelial basement membrane assembly and capillary tubule formation during wound healing. An in vitro model of endothelial basement membrane formation/capillary tubule formation, and an in vivo system of human angiogenesis model will be utilized to determine the significance of laminin 8 and laminin 10 in angiogenesis and granulation tissue formation during wound repair. We expect to obtain basic functional information about the cell- and ligand-binding properties of laminins8 and 10, and to demonstrate that these two laminins play important roles in one or more key steps of wound angiogenesis, including endothelial cell attachment, migration, basement membrane assembly and microvascular blood vessel formation. In addition, the studies are expected to have profound implications on the development of novel therapies directed at laminin components to improve angiogenesis and wound healing.
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