HEPARIN SEQUENCES FOR APPLICATIONS TO HEMOSTASIS

描述：肝素样糖胺聚糖（HLGAGs）是最酸性的 在细胞外基质中发现的天然生物聚合物。这些 复合多糖在调节生物活性方面起着关键作用 凝血级联反应和止血中的几种蛋白质。 HLGAGs的结构与活性之间的关系还很不清楚 由于这些聚合物的复杂性和不均匀性，它有 越来越明显的是，HLGAGs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活性 活动HLGAG寡糖的详细结构-活性研究 因为缺乏纯净的物质。由于复杂性和 这些多糖的异质性，目前，没有 制备确定的HLGAG低聚糖的可行方法。 确定HLGAGs的结构-活性关系， 为各种疾病发现新的治疗干预措施的机会 疾病状态。 首席研究员提出了一种全新的方法， 通过结合酶促反应产生确定的HLGAG寡糖， 用化学合成法降解天然肝素。该程序将绘制 从使用肝素酶酶促降解HLGAGs的广泛专业知识， 化学合成的复杂寡糖和理解 HLGAGs的生物活性。这种相对简单的合成策略 特别适用于确定的HLGAG的固相载体合成 序列，非常像肽和寡核苷酸，目前被组装。 这个新颖的跨学科计划最初将旨在提供一个 组装HLGAG序列的策略的原理证明， 凝血和止血过程。然而，临床机会的领域 HLGAGs的作用不仅限于止血，还包括血管生成和生长因子 介导的信号转导。

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.