In vitro synthesis of recombinant heparan sulfate
重组硫酸乙酰肝素的体外合成
基本信息
- 批准号:10218239
- 负责人:
- 金额:$ 46.37万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-02-13 至 2023-06-30
- 项目状态:已结题
- 来源:
- 关键词:AcetaminophenAcute Liver FailureAdvanced Glycosylation End ProductsAirAnimal ModelAnti-Inflammatory AgentsAntiinflammatory EffectBindingBinding ProteinsBiological AssayBuffaloesCell DeathCell surfaceCellsCessation of lifeCysteineDataDiseaseEnvironmentExtracellular MatrixFundingGoalsHMGB1 ProteinHeart failureHeparitin SulfateHepatocyteHistonesHospitalsHourImmune responseIn VitroInflammationInflammatoryInflammatory ResponseInjuryKnockout MiceLeadLiverLungMethodsMicroarray AnalysisModelingMolecularMusNecrosisNeutrophil InfiltrationNew YorkNorth CarolinaOligosaccharidesOverdosePatientsPatternPharmaceutical PreparationsPlayPolysaccharidesProcessProtective AgentsProteinsRecombinantsReperfusion InjuryResearchRoleS100A8 geneSiteSterilityStructureSulfateTechniquesTestingTherapeuticTherapeutic AgentsTissuesUniversitiesacetaminophen overdoseacute liver injurybasecell injurychemokinecytokinedrug developmenteffectiveness evaluationextracellularliver injuryliver transplantationmigrationmouse modelneutrophilpreventreceptorreceptor for advanced glycation endproductsresponsestandard caresuccesstissue repairtissue-repair responses
项目摘要
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.
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。
项目成果
期刊论文数量(137)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(3)
Disruption of PF4/H multimolecular complex formation with a minimally anticoagulant heparin (ODSH).
- DOI:10.1160/th11-11-0795
- 发表时间:2012-04
- 期刊:
- 影响因子:6.7
- 作者:Joglekar MV;Quintana Diez PM;Marcus S;Qi R;Espinasse B;Wiesner MR;Pempe E;Liu J;Monroe DM;Arepally GM
- 通讯作者:Arepally GM
Sequencing the Dermatan Sulfate Chain of Decorin.
- DOI:10.1021/jacs.7b10164
- 发表时间:2017-11-22
- 期刊:
- 影响因子:15
- 作者:Yu Y;Duan J;Leach FE 3rd;Toida T;Higashi K;Zhang H;Zhang F;Amster IJ;Linhardt RJ
- 通讯作者:Linhardt RJ
Chemoenzymatic synthesis of heparan sulfate and heparin oligosaccharides and NMR analysis: paving the way to a diverse library for glycobiologists.
- DOI:10.1039/c7sc03541a
- 发表时间:2017-12-01
- 期刊:
- 影响因子:8.4
- 作者:Zhang X;Pagadala V;Jester HM;Lim AM;Pham TQ;Goulas AMP;Liu J;Linhardt RJ
- 通讯作者:Linhardt RJ
Bioengineered heparins and heparan sulfates.
- DOI:10.1016/j.addr.2015.11.002
- 发表时间:2016-02-01
- 期刊:
- 影响因子:16.1
- 作者:Fu L;Suflita M;Linhardt RJ
- 通讯作者:Linhardt RJ
Directing the biological activities of heparan sulfate oligosaccharides using a chemoenzymatic approach.
使用化学酶方法指导硫酸乙酰肝素寡糖的生物活性。
- DOI:10.1093/glycob/cwr109
- 发表时间:2012
- 期刊:
- 影响因子:4.3
- 作者:Xu,Yongmei;Wang,Zhen;Liu,Renpeng;Bridges,ArleneS;Huang,Xuefei;Liu,Jian
- 通讯作者:Liu,Jian
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JIAN LIU其他文献
JIAN LIU的其他文献
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{{ truncateString('JIAN LIU', 18)}}的其他基金
The role of heparan sulfate in cathepsin K biology
硫酸乙酰肝素在组织蛋白酶 K 生物学中的作用
- 批准号:
10665752 - 财政年份:2022
- 资助金额:
$ 46.37万 - 项目类别:
Development of a New Carbohydrate-based Anticoagulant Drug
新型碳水化合物抗凝药物的开发
- 批准号:
9408360 - 财政年份:2017
- 资助金额:
$ 46.37万 - 项目类别:
PROBING HEPARIN STRUCTURAL ELEMENTS FOR HIGH RISK OF HEPARIN-INDUCED THROMBOCYTOP
探测肝素诱导血小板高风险的肝素结构元件
- 批准号:
8730574 - 财政年份:2013
- 资助金额:
$ 46.37万 - 项目类别:
Uncovering the controlling mechanisms in heparan sulfate biosynthesis
揭示硫酸乙酰肝素生物合成的控制机制
- 批准号:
8853290 - 财政年份:2013
- 资助金额:
$ 46.37万 - 项目类别:
Uncovering the controlling mechanisms in heparan sulfate biosynthesis
揭示硫酸乙酰肝素生物合成的控制机制
- 批准号:
8576941 - 财政年份:2013
- 资助金额:
$ 46.37万 - 项目类别:
PROBING HEPARIN STRUCTURAL ELEMENTS FOR HIGH RISK OF HEPARIN-INDUCED THROMBOCYTOP
探测肝素诱导血小板高风险的肝素结构元件
- 批准号:
9135956 - 财政年份:2013
- 资助金额:
$ 46.37万 - 项目类别:
PROBING HEPARIN STRUCTURAL ELEMENTS FOR HIGH RISK OF HEPARIN-INDUCED THROMBOCYTOP
探测肝素诱导血小板高风险的肝素结构元件
- 批准号:
8703471 - 财政年份:2013
- 资助金额:
$ 46.37万 - 项目类别:
PROBING HEPARIN STRUCTURAL ELEMENTS FOR HIGH RISK OF HEPARIN-INDUCED THROMBOCYTOP
探测肝素诱导血小板高风险的肝素结构元件
- 批准号:
9336703 - 财政年份:2013
- 资助金额:
$ 46.37万 - 项目类别:
Uncovering the controlling mechanisms in heparan sulfate biosynthesis
揭示硫酸乙酰肝素生物合成的控制机制
- 批准号:
8724523 - 财政年份:2013
- 资助金额:
$ 46.37万 - 项目类别:
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