ROLE OF LAMININ-5 IN IMPLANT ASSOCIATED ANGIOGENESIS

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The long term function of biomedical implants constructed from synthetic polymers is often compromised by inappropriate, uncontrolled tissue healing responses. The major focus of the proposed research is to evaluate mechanisms underlying the process of angiogenesis in tissue surrounding biomedical implants. Preliminary studies have established that implant associated angiogenesis can be modulated by treatment of the implant with specific extracellular matrix proteins. The major finding observed during preliminary studies was the ability of laminin type 5 treated polymers to stimulate angiogenesis in tissue surrounding the implants, as well as the accelerated formation of new blood vessels within porous, laminin 5 treated polymers. Laminin 5 treatment of polymers represents a novel means to alter the healing associated with biomedical implants providing a new direction toward long term function of implants. The major focus of the proposed studies will be to test the hypothesis that the angiogenesis and neovascularization responses associated with biomaterials modified with laminin 5 are dependent upon the endothelial cell integrin heterodimer alpha6beta4. Specific aim number 1 will examine the angiogenesis and neovascularization of polymers modified with the major extracellular matrix proteins involved in microvascular homeostasis as compared to laminin 5. Specific aim number 2 will evaluate the mechanisms underlying the activation of endothelial cells by laminin 5 resulting in two cell functions required in angiogenesis, namely adherence and migration. Specific aim number 3 will utilize DNA microarray technology to evaluate the mechanisms underlying laminin 5 dependent endothelial cell gene expression. An "angiogenesis chip" has been developed to simultaneously evaluate transcriptional control of 85 genes in cells and tissue associated with laminin 5 treated polymers. Specific aim number 4 will utilize a novel in vivo model of medical device function allowing the evaluation of laminin 5 mediated endothelialization of vascular grafts. Results from all these specific aims will provide an integrated evaluation of the role laminin 5 and the integrin alpha6beta4 in biomaterial associated angiogenesis.