3-O-sulfation of heparan sulfate as a regular of protein function
硫酸乙酰肝素的 3-O-硫酸化作为蛋白质功能的调节
基本信息
- 批准号:10615737
- 负责人:
- 金额:$ 45.17万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-05-01 至 2025-04-30
- 项目状态:未结题
- 来源:
- 关键词:AddressAnticoagulantsBindingBinding ProteinsBiologicalBiological ProcessBiologyBlood Coagulation FactorBlood coagulationCarbohydratesCell AdhesionCell surfaceCellsChemicalsCodeCollectionComplement ActivationComplexDeep Vein ThrombosisDisaccharidesDiseaseEndothelial CellsEndotheliumEngineeringEnzymatic BiochemistryEnzymesEpitopesExtracellular MatrixGene FamilyGoalsGrowth FactorHeparinHeparitin SulfateHumanInfectionInflammationInflammatoryIsoenzymesLeadLibrariesLifeLigandsMalignant NeoplasmsMammalian CellMediatingMethodologyMethodsMicro Array DataModalityModificationNerve DegenerationOligosaccharidesPolysaccharidesPrintingProtein IsoformsProteinsPulmonary EmbolismRecombinantsSignal TransductionSignaling ProteinSiteSpecificityStructureStructure-Activity RelationshipSubstrate SpecificitySulfateSurfaceTechnologyTherapeuticThromboembolismVascular DiseasesVertebral columncell typechemokinecytokinegain of functionhuman diseaseinterestmast cellmorphogenspathogenpreventprogramsprotein functionrecruitsulfotransferasetherapeutic lead compound
项目摘要
Project summary/abstract
Heparin is a highly sulfated carbohydrate produced by mast cells that is widely used as an anticoagulant
to prevent deep vein thrombosis, pulmonary embolism and arterial thromboembolism. Heparan sulfate
(HS) is structurally related to heparin and decorates the surface of all most all human cells. It interacts
with a multitude of proteins including chemokines and cytokines; blood coagulation factors; growth
factors and morphogens, proteins involved in complement activation, and cell adhesion and signaling
proteins. HS has been implicated in human diseases such as vascular diseases, inflammation,
infections and neurodegeneration. It has been postulated that HS encodes information by an ability to
recruit proteins in a context-dependent manner. Although the “HS-sulfate code” hypothesis is
conceptually appealing, little is known about the ligand specificities of HS binding proteins and the
substrate specificities of HS-biosynthetic enzymes. As a result, it is not known whether isoforms of HS
biosynthetic enzymes can create distinctive epitopes that in a cellular context can recruit specific HS-
binding proteins. An understanding of the specificities of HS binding also offers opportunities to develop
therapeutic modalities.
In this program, chemical and chemo-enzymatic methodologies will be developed that will make it
possible to prepare a focused library of biologically relevant HS epitopes with and without a 3-O-sulfate
moiety. These compounds will be used to develop an HS-microarray to establish ligand requirement of
HS-binding proteins. Compounds of interest will be further explored for their ability to interfere in the
binding and cellular activation of endothelial cells. We will focus on HS-binding proteins involved in blood
coagulation, inflammation and vascular disease. The established structure-activity relationships are
expected to provide therapeutic lead compounds. The HS-microarray will also be used as a general
platform to discover and characterize HS-binding proteins requiring a 3-O-sulfate. In addition, the
synthetic compounds will be used to define substrate requirements of the various 3-O-sulfotransferases.
Collectively, our studies will address the question of whether isoforms of 3-O-sulfotransferases can
create distinctive epitopes that can recruit specific HS-binding proteins, to mediate various biological
processes.
1
项目概要/摘要
肝素是一种由肥大细胞产生的高度硫酸化的碳水化合物,被广泛用作抗凝剂
预防深静脉血栓、肺栓塞和动脉血栓栓塞。硫酸乙酰肝素
(HS)在结构上与肝素相关,并装饰几乎所有人类细胞的表面。其交互
与多种蛋白质,包括趋化因子和细胞因子;凝血因子;生长
因子和形态发生素,参与补体激活的蛋白质,以及细胞粘附和信号传导
proteins. HS与人类疾病如血管疾病,炎症,
感染和神经退化。据推测,HS编码信息的能力,
以依赖于环境的方式募集蛋白质。虽然“HS-硫酸盐密码”假说是
虽然在概念上很吸引人,但对HS结合蛋白的配体特异性和HS结合蛋白的配体特异性知之甚少。
HS-生物合成酶的底物特异性。因此,尚不清楚HS的同种型是否
生物合成酶可以产生独特的表位,这些表位在细胞环境中可以募集特异性HS-
结合蛋白对HS结合特异性的理解也提供了发展
治疗方式
在这个程序中,化学和化学酶的方法将被开发,这将使它
可以制备具有和不具有3-O-硫酸酯的生物学相关HS表位的聚焦文库
部分。这些化合物将用于开发HS-微阵列,以确定免疫调节剂的配体需求。
HS结合蛋白。将进一步探索感兴趣的化合物的干扰细胞的能力。
内皮细胞的结合和细胞活化。我们将重点关注涉及血液中的HS结合蛋白
凝血、炎症和血管疾病。已建立的构效关系如下:
有望提供治疗先导化合物。HS-微阵列也将被用作一般的
该平台用于发现和表征需要3-O-硫酸盐的HS结合蛋白。此外该
将使用合成化合物来确定各种3-O-磺基转移酶的底物需求。
总的来说,我们的研究将解决3-O-磺基转移酶亚型是否可以
创造独特的表位,可以招募特异性HS结合蛋白,以介导各种生物学效应。
流程.
1
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Geert-Jan Boons其他文献
Geert-Jan Boons的其他文献
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{{ truncateString('Geert-Jan Boons', 18)}}的其他基金
Automated chemo-enzymatic synthesis of N-glycans for host-pathogen interactions
用于宿主-病原体相互作用的 N-聚糖自动化学酶合成
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10626153 - 财政年份:2022
- 资助金额:
$ 45.17万 - 项目类别:
Automated chemo-enzymatic synthesis of N-glycans for host-pathogen interactions
用于宿主-病原体相互作用的 N-聚糖自动化学酶合成
- 批准号:
10521604 - 财政年份:2022
- 资助金额:
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Synthetic multi-component influenza vaccines to elicit broad immunity
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$ 45.17万 - 项目类别:
3-O-sulfation of heparan sulfate as a regular of protein function
硫酸乙酰肝素的 3-O-硫酸化作为蛋白质功能的调节
- 批准号:
10400697 - 财政年份:2020
- 资助金额:
$ 45.17万 - 项目类别:
Streamlining the chemoenzymatic synthesis of asymmetrical glycans of biological importance
简化具有生物学重要性的不对称聚糖的化学酶合成
- 批准号:
9752086 - 财政年份:2016
- 资助金额:
$ 45.17万 - 项目类别:
Streamlining the chemoenzymatic synthesis of asymmetrical glycans of biological importance
简化具有生物学重要性的不对称聚糖的化学酶合成
- 批准号:
9533657 - 财政年份:2016
- 资助金额:
$ 45.17万 - 项目类别:
Streamlining the chemoenzymatic synthesis of asymmetrical glycans of biological importance
简化具有生物学重要性的不对称聚糖的化学酶合成
- 批准号:
9749989 - 财政年份:2016
- 资助金额:
$ 45.17万 - 项目类别:
Streamlining the chemoenzymatic synthesis of asymmetrical glycans of biological importance
简化具有生物学重要性的不对称聚糖的化学酶合成
- 批准号:
9166183 - 财政年份:2016
- 资助金额:
$ 45.17万 - 项目类别:
Mammalian Glycosyltransferases for use in Chemistry and Biology
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- 批准号:
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- 资助金额:
$ 45.17万 - 项目类别:
Mammalian Glycosyltransferases for use in Chemistry and Biology
用于化学和生物学的哺乳动物糖基转移酶
- 批准号:
8740506 - 财政年份:2013
- 资助金额:
$ 45.17万 - 项目类别:
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