HEPARIN SEQUENCES FOR APPLICATIONS TO HEMOSTASIS

描述：类肝素糖胺聚糖(HLGAGs)是酸性最强的 天然生物聚合物，存在于细胞外基质中。这些 复合多糖在生物活性调节中起着关键作用。 凝血级联和止血中的几种蛋白质。 HLGAGs的结构和活性之间的关系仍然很差 由于这些聚合物的复杂性和异质性而被理解。它有 越来越明显的是，HLGAG的定义长度和序列是 负责与特定蛋白质结合并调节其生物学特性 活动。HLGAG寡糖的详细构效研究 因为缺乏纯净的材料而苦恼。由于它的复杂性和 目前，这些多糖的异质性不存在 制备确定的HLGAG寡糖的可行方法。 确定HLGAGs的结构-活性关系创建了 为各种疾病发现新的治疗干预措施的机会 疾病状态。 首席调查员提出了一种全新的方法来研究 结合酶法制备确定的HLGAG寡糖 化学合成法降解天然肝素。该程序将绘制 在使用肝素酶对HLGAGs进行酶降解方面的丰富专业知识， 复杂低聚糖的化学合成及对低聚糖的认识 HLGAGs的生物学活性。这个相对简单的综合策略 将特别适合于定义的HLGAG的固体载体合成 序列，很像多肽和寡核苷酸，目前正在组装。 这一新颖的跨学科计划最初的目的是提供 组装HLGAG序列策略的原则证明 凝血和止血过程。然而，临床机会的领域 HLGAGs不仅止血，还可以包括血管生成和生长因子 中介信号转导。

DESCRIPTION: Heparin-like glycosaminoglycans (HLGAGs) are the most acidic naturally occurring biopolymers, found in the extracellular matrices. These complex polysaccharides play a key role in regulating the biological activity of several proteins in the coagulation cascade and in hemostasis. The relationship between structure and activity of HLGAGs is still very poorly understood due to the complexity and heterogeneity of these polymers. It has become increasingly evident that defined lengths and sequences of HLGAGs are responsible for binding to a particular protein and modulating its biological activity. Detailed structure-activity studies on HLGAG oligosaccharides have suffered from the lack of pure material. Due to the complexity and heterogeneity of these polysaccharides there are, at the present time, no feasible approaches for the preparation of defined HLGAG oligosaccharides. Determination of structure-activity relationships of HLGAGs creates an opportunity for the discovery of novel therapeutic interventions for a variety of disease states. The principal investigator's present an entirely novel approach to the generation of defined HLGAG oligosaccharides by combining the enzymatic degradation of natural heparin with chemical synthesis. The program will draw from extensive expertise in enzymatic degradation of HLGAGs using heparinases, chemical synthesis of complex oligosaccharides and an understanding of the biological activities of HLGAGs. This relatively simple synthetic strategy would particularly lend itself to the solid support synthesis of defined HLGAG sequences, much like peptides and oligonucleotides are currently assembled. This novel and interdisciplinary program initially will be aimed at providing a proof-of-principle for the strategy to assemble HLGAG sequences involved in coagulation and hemostasis processes. However, areas of clinical opportunities of HLGAGs go beyond hemostasis, and can include angiogenesis and growth factor mediated signal transduction.