Evolving New Glycosaminoglycan Mimetics
不断发展的新糖胺聚糖模拟物
基本信息
- 批准号:9789672
- 负责人:
- 金额:$ 37.64万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-09-25 至 2022-07-31
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAffinityAlzheimer&aposs DiseaseAnti-inflammatoryAnticoagulantsAntithrombin IIIArchitectureAutoimmune DiseasesAvidityBindingBinding ProteinsBinding SitesBiological ProcessBiological Response ModifiersBlood coagulationCXCL10 geneCXCL11 geneCXCL9 geneCXCR3 geneCell ProliferationCell divisionCellsChemicalsChemotaxisChondroitin SulfatesCollaborationsCommunicable DiseasesConsumptionDementiaDevelopmentDirected Molecular EvolutionDisaccharidesDiseaseDrug TargetingEpitopesEventFGF2 geneGlycopeptidesGlycosaminoglycansGoalsGrowth FactorHIVHeparinHeparitin SulfateImmune responseIn VitroIndividualInflammationInflammation MediatorsInflammatoryLaboratoriesLeadLibrariesMacular degenerationMalignant NeoplasmsMediatingMessenger RNAMethodsMicrotubule-Associated ProteinsNeoplasm MetastasisNerve DegenerationNeurodegenerative DisordersNeuronsOligosaccharidesParkinson DiseasePathogenesisPathogenicityPathologicPathologic ProcessesPathologyPeptidesPharmaceutical PreparationsPhysiologicalPhysiological ProcessesPlayPolymersPolysaccharidesProteinsRANTESResearchRoleSamplingSignal PathwaySignal TransductionSignaling ProteinStructureStructure-Activity RelationshipTestingTherapeuticTherapeutic StudiesTimeTranslationsUnspecified or Sulfate Ion SulfatesVariantWorkWound Healingangiogenesisbasecell motilitychemokinehuman diseaseimmunoregulationin vivoinsightinterestlink proteinmigrationmimeticsmonomernanomolarneurodevelopmentneuronal growthneutralizing antibodynovelnovel strategiesnovel therapeutic interventionnovel therapeuticspathogenpolymerizationpreferenceprotein aminoacid sequenceprotein complexreceptorscaffoldstemsulfationtau Proteinstau interactiontooltransmission processuptake
项目摘要
Project Summary
Glycosaminoglycans (GAGs) play important roles in many physiological and pathological events
such as cell division, inflammation, neural development, and cancer metastasis. The long
polysaccharide chains of GAGs contain various sulfated disaccharides that are organized into
sulfate-rich and under-sulfated domains. This rich structural diversity enables GAGs such as
heparan sulfate (HS) to interact with numerous proteins and regulate key signaling pathways.
However, efforts to understand their structure-function relationships and harness their
therapeutic potential have been hampered by the chemical complexity of GAGs and a lack of
tools. At present, there are no tools to manipulate the interactions of GAGs with specific proteins
of interest, thus complicating efforts to pinpoint their precise roles. The goal of this project is to
develop novel chemical probes for selectively modulating GAG activity. We will use a directed
evolution-based approach to create a new class of GAG mimetics – multivalent glycopeptides
appended with short, active HS motifs – to modulate specific HS-protein interactions. Random
sampling of peptide sequences by directed evolution should allow for the selection of structures
containing the ideal number and arrangement of HS motifs. In addition to optimal HS clustering,
selected peptides should contain peptide motifs recognized by the protein of interest, thus
generating highly specific GAG probes. In Aim 1, we will work in collaboration with the Krauss
laboratory to develop the approach and generate HS mimetics that interact selectively with
fibroblast growth factor 2 (FGF2), a key growth factor involved in cell migration, angiogenesis,
and differentiation. In Aim 2, we will evolve glycopeptides that bind to specific forms of tau, a
microtubule-associated protein linked to dementias such as Alzheimer's disease and
Parkinson's disease. We will use these HS mimetics to understand the mechanisms underlying
tau uptake into neurons and neurodegeneration. In addition, we will explore whether our
mimetics can block the intercellular spreading of tau and its pathogenic consequences. In Aim 3,
we will evolve glycopeptides that bind chemokines (specifically CXCL9, CXCL10 and CXCL11),
a class of therapeutically important proteins that are key mediators of inflammation. Our probes
should provide unique insights into the paradoxical functional redundancy of chemokines,
enabling us to tease apart their individual roles. Together, these studies will produce a novel
class of GAG-based probes for understanding the physiological functions of GAGs and may
ultimately lead to new therapeutic leads or approaches to diseases such as cancer,
neurodegenerative diseases, inflammatory and autoimmune disorders, and infectious diseases.
项目总结
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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Linda C Hsieh-Wilson其他文献
Chemical approaches to understanding O-GlcNAc glycosylation in the brain
理解大脑中 O-GlcNAc 糖基化的化学方法
- DOI:
10.1038/nchembio.68 - 发表时间:
2008-01-17 - 期刊:
- 影响因子:13.700
- 作者:
Jessica E Rexach;Peter M Clark;Linda C Hsieh-Wilson - 通讯作者:
Linda C Hsieh-Wilson
Linda C Hsieh-Wilson的其他文献
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{{ truncateString('Linda C Hsieh-Wilson', 18)}}的其他基金
Expedited Synthesis of Glycosaminoglycans Containing Defined Sulfation Domains
含有特定硫酸化结构域的糖胺聚糖的快速合成
- 批准号:
8985640 - 财政年份:2015
- 资助金额:
$ 37.64万 - 项目类别:
A chemical approach to elucidating the structure-function relationships of chondr
阐明软骨结构与功能关系的化学方法
- 批准号:
8220729 - 财政年份:2010
- 资助金额:
$ 37.64万 - 项目类别:
A chemical approach to elucidating the structure-function relationships of chondr
阐明软骨结构与功能关系的化学方法
- 批准号:
7918318 - 财政年份:2010
- 资助金额:
$ 37.64万 - 项目类别:
A chemical approach to elucidating the structure-function relationships of chondronitin sulfate glycosaminoglycans
阐明硫酸软骨素糖胺聚糖结构与功能关系的化学方法
- 批准号:
9134776 - 财政年份:2010
- 资助金额:
$ 37.64万 - 项目类别:
A chemical approach to elucidating the structure-function relationships of chondr
阐明软骨结构与功能关系的化学方法
- 批准号:
8423815 - 财政年份:2010
- 资助金额:
$ 37.64万 - 项目类别:
A chemical approach to elucidating the structure-function relationships of chondronitin sulfate glycosaminoglycans
阐明硫酸软骨素糖胺聚糖结构与功能关系的化学方法
- 批准号:
8965476 - 财政年份:2010
- 资助金额:
$ 37.64万 - 项目类别:
A chemical approach to elucidating the structure-function relationships of chondr
阐明软骨结构与功能关系的化学方法
- 批准号:
8053893 - 财政年份:2010
- 资助金额:
$ 37.64万 - 项目类别:
Role of Fucosyl Saccharides and O-GlcNAc Glycosylation in Neuronal Communication
岩藻糖基糖和 O-GlcNAc 糖基化在神经元通讯中的作用
- 批准号:
7846392 - 财政年份:2009
- 资助金额:
$ 37.64万 - 项目类别:
Role of Fucosyl Saccharides in Neuronal Communication
岩藻糖基糖在神经元通讯中的作用
- 批准号:
6747556 - 财政年份:2003
- 资助金额:
$ 37.64万 - 项目类别:
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