In vitro synthesis of recombinant heparan sulfate
In vitro synthesis of recombinant heparan sulfate
批准号:
10218239
负责人:
JIAN LIU
金额:
$46.37万
依托单位国家:
美国
项目类别:
财政年份:
2009
资助国家:
美国
项目状态:
已结题
起止时间:
2009-02-13 至 2023-06-30
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
中文摘要
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
英文摘要
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.
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DOI:
10.1016/j.addr.2015.11.002
发表时间:
2016-02-01
期刊:
Advanced drug delivery reviews
影响因子:
16.1
作者:
[Fu L, Suflita M, Linhardt RJ]
通讯作者:
Linhardt RJ
DOI:
10.1160/th11-11-0795
发表时间:
2012-04
期刊:
Thrombosis and haemostasis
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
DOI:
10.1021/jacs.7b10164
发表时间:
2017-11-22
期刊:
Journal of the American Chemical Society
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
DOI:
10.1039/c7sc03541a
发表时间:
2017-12-01
期刊:
Chemical science
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
DOI:
10.1039/d0cb00199f
发表时间:
2021-02-22
期刊:
RSC chemical biology
影响因子:
4.1
作者:
[Wang Z, Arnold K, Dhurandhare VM, Xu Y, Liu J]
通讯作者:
Liu J
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