In vitro synthesis of recombinant heparan sulfate

摘要 该建议旨在开发一种方法来合成结构定义的 作为治疗剂的乙酰肝素硫酸化寡糖。在目前的供资周期中， 我们建议研究硫酸乙酰肝素在抑制炎症反应中的作用。 该项目是三个研究小组的合作成果，包括刘健博士 （北卡罗来纳州大学）、Rafal Pawlinski博士（北卡罗来纳州大学）和Dr. 丁旭（州立大学纽约布法罗分校）。对乙酰氨基酚过量导致 肝细胞损伤，引发炎症反应进行组织修复。 然而，如果这种反应过度，它会导致对肝脏问题的附带损害， 导致急性肝损伤肝损伤加重导致心肺功能衰竭， 最终导致死亡我们发现了一种结构均匀的硫酸乙酰肝素 十八糖（18-mer）对肝损伤有较强的保护作用 对乙酰氨基酚的作用。提出了三个具体目标，以了解 18-mer保护效果背后的细节。目标1是确定 18-mer的作用。目的2是确定硫酸乙酰肝素对 肝保护作用的微阵列分析。目的三是确定疗效 对乙酰氨基酚引起的肝损伤的延迟治疗，目的是扩大 治疗窗口因为不受控制的炎症是导致许多 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.