Development of materials to release bioactive lipids

描述（由申请人提供）：生物活性脂质已成为细胞内和细胞外信号传导的关键因素。具有生物活性的脂质鞘氨醇1-磷酸（S1 P）能引起内皮细胞的强烈反应。S1 P对内皮细胞的强大作用表明，S1 P的控制递送可能有利于促进人工材料的内皮化。与蛋白质生长因子不同，S1 P可以在材料中通过酶促作用从血液中已经存在的鞘氨醇中产生。 我们先前已经合成了聚乙二醇材料，其强烈抵抗蛋白质吸附和血细胞粘附，但由于细胞粘附肽的存在而允许内皮细胞粘附。该材料用作与动物内皮化相关的假内膜的工程模拟物。然而，我们的涂层不会促进凝血和血栓形成，因此可以用作小直径血管移植物的涂层。 在拟议的研究中，我们将表征新材料，S1 P释放的机制以及S1 P递送对细胞粘附和迁移的影响。该研究项目的具体目标是： 目的1：证明S1 P释放动力学由脂质结合蛋白通过水凝胶的扩散速率决定。 目标二：确定S1 P的受控递送是否允许在PEG水凝胶中使用更高浓度的RGD肽，这可能增加长期细胞粘附强度。 目的3：证明酶促生产允许从纳米级PEG涂层递送S1 P。目的4：评价含有RGD-肽的释放S1 P的PEG涂层在大鼠颈动脉中的安全性和有效性。

DESCRIPTION (provided by applicant): Bioactive lipids have emerged as critical factors in intra- and extracellular signaling. The bioactive lipid sphingosine 1-phosphate (S1P) elicits powerful responses from endothelial cells. The potent effects of S1P on endothelial cells suggest that controlled delivery of S1P may be beneficial in promoting the endothelialization of artificial materials. Unlike protein growth factors, S1P can be produced within materials enzymatically, from sphingosine that is already present in blood. We have previously synthesized polyethylene glycol materials that strongly resist protein adsorption and blood cell adhesion, but allow endothelial cell adhesion due to the presence of cell adhesion peptides. The materials function as an engineered mimic of the pseudointima that is associated with endothelialization in animals. However, our coatings will not promote coagulation and thrombosis and thus could be used as a coating for small diameter vascular grafts. In the proposed studies, we will characterize the new materials, the mechanism of S1P release and the effect of S1P delivery on cell adhesion and migration. The specific aims of this research project are: Aim 1: Demonstrate that S1P release kinetics are determined by the rate of diffusion of lipid-binding proteins through the hydrogel. Aim 2: Determine if controlled delivery of S1P allows the use of higher concentrations of RGD peptides in the PEG hydrogels, which may increase long-term cell adhesion strength. Aim 3: Demonstrate that enzymatic production allows delivery of S1P from nanoscale PEG coatings. Aim 4: Evaluate the safety and efficacy of S1 P-releasing PEG coatings containing RGD-peptide in the rat carotid artery.