Development of materials to release bioactive lipids

开发释放生物活性脂质的材料

• 批准号: 7636742
• 负责人: DONALD L ELBERT
• 金额: $ 36.18万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7636742
• 关键词: Abbreviations; Accounting; Adsorption; Amino Acid Sequence; Angiogenic Factor; Animals; Binding Proteins; Blood; Blood Cells; Blood Platelets; Blood flow; Bovine Serum Albumin; Caliber; Carotid Arteries; Cell Adhesion; Cell Survival; Cell physiology; Coagulation Process; Conflict (Psychology); Development; Diffusion; Embryo; Endothelial Cells; Engineering; Equilibrium; G-Protein-Coupled Receptors; Growth Factor; High Density Lipoproteins; Human; Hydrogels; Integrins; Kinetics; Knock-out; Ligands; Lipid Binding; Lipids; Liquid substance; Mechanics; Mus; Peptides; Physiological; Plasma; Platelet Activation; Polyethylene Glycols; Polyethylene Terephthalates; Production; Proteins; RGD (sequence); Rattus; Recombinants; Research Personnel; Research Project Grants; Safety; Serum; Signal Transduction; Smooth Muscle Myocytes; Sphingosine; Sphingosine-1-Phosphate Receptor; Surface; Thrombosis; Tumor Angiogenesis; Vascular Endothelial Growth Factors; Vascular Graft; cell motility; extracellular; migration; nanoscale; programs; pseudointima; receptor; response; shear stress; sphingosine 1-phosphate

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.

描述(申请人提供)：生物活性脂类已经成为细胞内和细胞外信号传递的关键因素。生物活性脂鞘氨醇1-磷酸(S1P)可引起内皮细胞的强烈反应。S1P对内皮细胞的有效作用表明，S1P的受控释放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，S1P可以在材料中通过酶作用从血液中已经存在的鞘氨醇中产生。 我们之前已经合成了聚乙二醇类材料，这种材料强烈抵抗蛋白质吸附和血细胞黏附，但由于细胞黏附肽的存在而允许内皮细胞黏附。这种材料的功能是对与动物内皮化相关的假内膜进行工程模拟。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，我们将对新材料、S1P的释放机制以及S1P对细胞黏附和迁移的影响进行表征。这项研究项目的具体目标是： 目的1：证明S1P的释放动力学由脂结合蛋白在水凝胶中的扩散速度决定。 目的2：确定S1P的受控释放是否允许在聚乙二醇水凝胶中使用更高浓度的RGD多肽，这可能会增加细胞的长期黏附强度。 目的3：证明酶法生产可以从纳米级的聚乙二醇膜中传递S1P。目的：评价含RGD多肽的聚乙二醇S1 P缓释涂层对大鼠颈动脉的安全性和有效性。