Exploring Siglec-glycan ligand interactions using chemoenzymatic approaches
使用化学酶方法探索 Siglec-聚糖配体相互作用
基本信息
- 批准号:10297728
- 负责人:
- 金额:$ 81.53万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-06-04 至 2026-05-31
- 项目状态:未结题
- 来源:
- 关键词:2019-nCoVAdvanced Malignant NeoplasmAffinityAnti-Inflammatory AgentsBindingBinding ProteinsBiochemical GeneticsCTLA4 geneCancer PatientCell DeathCell LineCell surfaceCellsClinicalClinical TrialsDevelopmentElementsEngineeringEpitopesFDA approvedFamilyGoalsImmuneImmune checkpoint inhibitorImmune signalingImmune systemImmunoglobulinsImmunotherapyInflammationInflammatoryLectinLigand BindingLigandsMalignant NeoplasmsMediatingMembrane GlycoproteinsModalityMolecularMyeloid CellsNatural Killer CellsPathologyPatientsPatternPolysaccharidesProcessProteinsReceptor ActivationRegulationRelapseReporterRoleSARS-CoV-2 infectionSialic AcidsSideSignal TransductionSyndromeT-LymphocyteTestingTherapeuticTherapeutic AgentsToxic effectTumor ImmunityTyrosineVirus DiseasesXenograft Modelanti-PD-1anti-cancerbasecancer therapycancer typecell killingcytotoxiccytotoxicitydesignglycosylationimmune activationimmune checkpointimmune checkpoint blockadeimmunological synapseimmunoregulationinventionmacrophagemast cellnanoparticleneoplastic cellnovel therapeuticsprogrammed cell death protein 1receptorreceptor bindingrecruitresponsesialic acid binding Ig-like lectintooltumor
项目摘要
PROJECT SUMMARY/ABSTRACT
Regulation of the immune system is substantially influenced by glycosylation. Cell-surface glycans tune
ligand-receptor binding and set a threshold for initiating the downstream signaling for immune cell activation.
Siglecs (sialic acid-binding immunoglobulin-type lectins) are a family of regulatory receptors involved in these
processes. A Siglec can bind to both cis and trans sialylated glycan ligands that are expressed on the same or
interacting cells, respectively. The binding of Siglecs with their ligands can either segregate Siglecs from
activation receptors or move them closer. The ability of inhibitory Siglecs to modulate activation receptors is
regulated by spatial proximity: recruiting Siglecs to the immune synapse in the proximity of activation receptors
would trigger inhibitory signaling to suppress immune-system activation, whereas moving Siglecs away from
activation receptors would enable optimal signaling through activation receptors.
For the above reasons, recently, Siglecs have been described as glyco-immune checkpoints. Through
their interaction with sialylated glycans aberrantly expressed on tumor cells, innate immune cell-associated
Siglecs trigger signaling cascades to inhibit immune-system activation. Likewise, Siglecs upregulated on tumor
cells interact with yet-to-be identified T-cell membrane glycoproteins to suppress T cell anti-tumor functions.
On the positive side, however, inhibitory signaling through Siglecs curbs inflammation during cell death
induced by viral infection. Despite these intriguing observations, the mechanisms underlying the above
processes are just starting to be elucidated.
The overarching goal of this project is to use a combination of chemoenzymatic, biochemical and
genetic tools to explore Siglec-glycan ligand interactions and their therapeutic implication. In Aim 1, we will
design Siglec-based chimeric switch receptors and convert inhibitory Siglecs into activation receptors. In Aim
2, we will use a cell-based glycan array platform to screen for high-affinity and specific ligands of Siglecs. Once
identified, we will explore their utilities to suppress or harness the inhibitory Siglec signaling for therapeutic
applications. Finally, we will use our chemoenzymatic tools to investigate how the Siglec-cis ligand interaction
is involved in mediating the Siglec–trans ligand interaction and accordingly immune cell activation (Aim 3).
项目摘要/摘要
免疫系统的调节在很大程度上受到糖基化的影响。细胞表面糖链的调节
配体-受体结合,并为启动免疫细胞激活的下游信号设定阈值。
Siglecs(唾液酸结合免疫球蛋白-型凝集素)是一类与此相关的调节受体家族。
流程。Siglec可以与顺式和反式唾液酸化的葡聚糖配体结合,这些配体表达在同一或
相互作用的细胞。Siglecs与其配体的结合可以将Siglecs与其配体分离
激活感受器或将它们移动得更近。抑制性Siglecs调节激活受体的能力是
空间邻近调节:在激活受体附近将Siglecs重新招募到免疫突触
会触发抑制信号来抑制免疫系统的激活,而将Siglecs从
激活受体将通过激活受体实现最佳信号传递。
由于上述原因,最近,Siglecs被描述为糖免疫检查点。穿过
它们与唾液酸糖的相互作用在肿瘤细胞上异常表达,与天然免疫细胞相关
Siglecs触发信号级联以抑制免疫系统的激活。同样,Siglecs上调了肿瘤的表达
细胞与待鉴定的T细胞膜糖蛋白相互作用,抑制T细胞的抗肿瘤功能。
然而,积极的一面是,通过Siglecs的抑制信号抑制了细胞死亡期间的炎症
由病毒感染引起的。尽管有这些耐人寻味的观察,但上述现象背后的机制
这一过程才刚刚开始被阐明。
这个项目的首要目标是使用化学酶、生化和
探索Siglec-葡聚糖配基相互作用及其治疗意义的遗传工具。在目标1中,我们将
设计基于Siglec的嵌合开关受体,将抑制性Siglecs转化为激活受体。在AIM
2,我们将使用基于细胞的多糖阵列平台来筛选Siglecs的高亲和力和特异性配体。一次
我们将探索它们抑制或利用抑制性Siglec信号用于治疗的效用
申请。最后,我们将使用我们的化学酶工具来研究Siglec-cis配体之间的相互作用
参与调节Siglec-反式配体的相互作用,从而激活免疫细胞(目标3)。
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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Peng Wu的其他文献
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{{ truncateString('Peng Wu', 18)}}的其他基金
Chemoenzymatic glycan editing for deciphering biological functions of glycans
化学酶聚糖编辑破译聚糖的生物学功能
- 批准号:
10555320 - 财政年份:2021
- 资助金额:
$ 81.53万 - 项目类别:
Exploring Siglec-glycan ligand interactions using chemoenzymatic approaches
使用化学酶方法探索 Siglec-聚糖配体相互作用
- 批准号:
10621946 - 财政年份:2021
- 资助金额:
$ 81.53万 - 项目类别:
Chemoenzymatic glycan editing for deciphering biological functions of glycans
化学酶聚糖编辑破译聚糖的生物学功能
- 批准号:
10799053 - 财政年份:2021
- 资助金额:
$ 81.53万 - 项目类别:
Exploring Siglec-glycan ligand interactions using chemoenzymatic approaches
使用化学酶方法探索 Siglec-聚糖配体相互作用
- 批准号:
10417251 - 财政年份:2021
- 资助金额:
$ 81.53万 - 项目类别:
Chemoenzymatic glycan editing for deciphering biological functions of glycans
化学酶聚糖编辑破译聚糖的生物学功能
- 批准号:
10329937 - 财政年份:2021
- 资助金额:
$ 81.53万 - 项目类别:
Chemical Tools for Studying Fucosylated Glycans
用于研究岩藻糖基化聚糖的化学工具
- 批准号:
9320789 - 财政年份:2016
- 资助金额:
$ 81.53万 - 项目类别:
Chemical Tools for Studying Fucosylated Glycans
用于研究岩藻糖基化聚糖的化学工具
- 批准号:
9105947 - 财政年份:2016
- 资助金额:
$ 81.53万 - 项目类别:
Chemoenzymatic methods for the detection of cell-surface glycans
检测细胞表面聚糖的化学酶法
- 批准号:
8964803 - 财政年份:2015
- 资助金额:
$ 81.53万 - 项目类别:
Chemical tools for studying fucosylated glycans
研究岩藻糖基化聚糖的化学工具
- 批准号:
8535787 - 财政年份:2010
- 资助金额:
$ 81.53万 - 项目类别:
Chemical tools for studying fucosylated glycans
研究岩藻糖基化聚糖的化学工具
- 批准号:
8326225 - 财政年份:2010
- 资助金额:
$ 81.53万 - 项目类别: