ROLE OF LAMININ-5 IN IMPLANT ASSOCIATED ANGIOGENESIS

由合成聚合物构建的生物医学植入物的长期功能经常受到不适当的、不受控制的组织愈合反应的损害。本研究的主要重点是评估生物医学植入物周围组织血管生成过程的机制。初步研究表明，植入物相关的血管生成可以通过特定的细胞外基质蛋白处理来调节。在初步研究中观察到的主要发现是层粘连蛋白5处理过的聚合物能够刺激植入物周围组织的血管生成，以及在多孔的层粘连蛋白5处理过的聚合物中加速新血管的形成。聚合物的层粘连蛋白5处理是改变生物医学植入物愈合的一种新方法，为植入物的长期功能提供了新的方向。本研究的主要重点是验证一种假设，即与层粘连蛋白5修饰的生物材料相关的血管生成和新生血管反应依赖于内皮细胞整合素异源二聚体alpha6beta4。具体目标1将检查与微血管稳态相关的主要细胞外基质蛋白修饰的聚合物与层粘连蛋白5的血管生成和新生血管形成。特异性目标2将评估层粘连蛋白5激活内皮细胞的机制，从而导致血管生成所需的两种细胞功能，即粘附和迁移。特异性目标3将利用DNA微阵列技术来评估层粘连蛋白5依赖性内皮细胞基因表达的机制。一种“血管生成芯片”已经开发出来，可以同时评估与层粘连蛋白5处理的聚合物相关的细胞和组织中的85个基因的转录控制。特异性目标4将利用一种新的医疗器械功能体内模型，允许评估层粘连蛋白5介导的血管移植内皮化。所有这些特定目标的结果将为层粘连蛋白5和整合素alpha6beta4在生物材料相关血管生成中的作用提供一个综合评价。

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.