In vitro synthesis of recombinant heparan sulfate

摘要 这项提议的目的是开发一种合成结构定义的 乙酰肝素硫酸酯低聚糖作为治疗剂。在当前的筹资周期中， 我们建议研究硫酸乙酰肝素在抑制炎症反应中的作用。 这个项目是包括刘健博士在内的三个研究小组的共同努力 Rafal Pawlinski博士(北卡罗来纳大学)和Dr Rafal Pawlinski(北卡罗来纳大学) 丁旭(纽约州立大学布法罗分校)。扑热息痛过量致病原因 肝细胞损伤，触发组织修复的炎症反应。 然而，如果这种反应过度，就会对肝脏造成附带损害， 导致急性肝脏损伤。肝脏损伤加剧会导致心肺衰竭， 最终导致死亡。我们发现了一种结构均一的硫酸乙酰肝素 十八糖(18-mer)对实验性肝损伤具有较强的保护作用 在小鼠模型中使用扑热息痛。提出了三个具体的目标来理解 18-mer保护效果背后的细节。目标1是确定以下目标 18-聚体的作用。目的2是测定硫酸乙酰肝素的结构选择性 用基因芯片分析保肝作用。目标3是确定疗效 对对乙酰氨基酚所致肝损伤的延迟治疗，目的是扩大 治疗窗口。因为失控的炎症是导致许多 疾病，我们的研究结果将促进抗炎药物的开发 聚焦硫酸乙酰肝素分子。

Abstract This proposal is aimed to develop a method to synthesize structurally defined heparan sulfated oligosaccharides as therapeutic agents. In the current funding cycle, we propose to study the role of heparan sulfate in dampening inflammatory responses. This project is a collaborative effort of three research groups, including Dr. Jian Liu (University of North Carolina), Dr. Rafal Pawlinski (University of North Carolina), and Dr. Ding Xu (State University of New York at Buffalo). Acetaminophen overdose causes hepatocyte cell damage that triggers inflammatory responses for tissue repairing. However, if this response overreacts, it causes to collateral damages to the liver issues, leading to acute liver injury. Escalated liver injury leads to the failure of heart and lung, and ultimately death. We discover a structurally homogeneous heparan sulfate octadecasaccharide (18-mer) displays strong protection effect for the liver injury induced by acetaminophen in a murine model. Three specific aims are proposed to understand the details behind the 18-mer’s protection effect. Aim 1 is to determine the targets for the effect of 18-mer. Aim 2 is to determine the structural selectivity of heparan sulfate for the hepatoprotection effect using microarray analysis. Aim 3 is to determine the efficacy for the delayed treatment for acetaminophen-induced liver injury with a goal to widen the therapeutic window. Because uncontrolled inflammation is a major contributor to many diseases, results from our studies will advance anti-inflammatory drug development focusing heparan sulfate molecules.