Biofunctional Materials Containing Protein Mimetics

描述(由申请人提供)：巨噬细胞是指导宿主-生物材料相互作用和许多疾病病因的中心。我们假设仿生寡肽可以从巨噬细胞活性蛋白(纤维连接蛋白和Interdeukin-1)的功能结构中设计出来，并用于探索配体-受体相互作用和连接后事件，作为寻求更好地了解参与巨噬细胞行为的分子调控机制的基础。此外，这些多肽被用作平台技术的一个组成部分，用于开发新的生物材料，在体外和体内部分调节巨噬细胞的功能。在竞争更新申请的重新提交中，我们假设观察到的肽介导的巨噬细胞行为是由于表面固定时的优先配体构象和调节巨噬细胞功能的多个细胞内事件的存在所致。为了达到这些目标，我们制定了三个相互关联的目标：(1)确定固定在不同化学底物(TCPS，单甲氧基-聚乙二醇单丙烯酸酯-共聚丙烯酸-共四羟甲基丙酸乙酯的共聚物，以及含有化学修饰的明胶和聚乙二醇二丙烯酸酯的互穿网络)上的多肽构象，并将这种结构与配体-整合素识别和结合联系起来；(2)鉴定细胞内酪氨酸磷酸化蛋白，可选择的连接后连接后的细胞内途径，连接后的基因表达和细胞功能，(3)对巨噬细胞活性寡肽与整合素的结合动力学进行定量和建模并在多肽-整合素络合时与鉴定的磷酸化整合素相关蛋白相互作用。我们在探索材料-巨噬细胞相互作用的分子机制方面所做的持续努力，已经对配体-受体结合和吞噬细胞功能的调节途径提供了见解，这是理解生物医学设备的宿主-材料相互关系的基础。

DESCRIPTION (provided by applicant): Macrophages are central in directing host-biomaterial interaction and many disease etiologies. We hypothesized that biomimetic oligopeptides can be designed from the functional structure of macrophage-active proteins (fibronectin and intedeukin-1) and employed to probe the ligand-receptor interaction and post-ligation events as a basis for seeking a greater understanding in the molecular control mechanism involved in macrophage behavior. Furthermore, these peptides were utilized as a component of a platform technology in the development of novel biomaterials to partly modulate macrophage function in vitro and in vivo. In this resubmission of the competing renewal application, we hypothesize that the observed peptide-mediated macrophage behavior is contributed by the preferential ligand conformation upon surface immobilization and the presence of multiple intracellular events in regulating macrophage function. To address these goals, three interrelated aims are formulated: (1) to determine the peptide conformation upon immobilization onto chemically distinct substrates (TCPS, copolymer of monomethoxy-PEG-monoacrylate-colacrylic acid-co-tetramethylolpropylacrylate, and interpenetrating networks containing chemically modified gelatin and polyethyleneglycol-diacrylate) and to correlate this structure with ligand-integrin recognition and binding, (2) to identify intracellular tyrosine phosphorylated proteins, alternative post-ligation intracellular pathways, post-ligation gene expression and cellular function in peptide-mediated adherent macrophages using mono- and co-culture systems, (3) to quantify and model the binding kinetics of macrophage-active oligopeptides with integrins, and to correlate with the identified phosphorylated integrin-associated proteins upon peptide-integrin complexation. Our continuing effort in probing the molecular mechanism of material-macrophage interaction has shed insights on ligand-receptor association and regulation pathways for phagocytic cell function, that are fundamental in understanding the host-material interrelationship for biomedical devices.