权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
Peng Wu
金额：
$ 81.53万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
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：
https://reporter.nih.gov/project-details/10297728
关键词：
2019-nCoV Advanced Malignant Neoplasm Affinity Anti-Inflammatory Agents Binding Binding Proteins Biochemical Genetics CTLA4 gene Cancer Patient Cell Death Cell Line Cell surface Cells Clinical Clinical Trials Development Elements Engineering Epitopes FDA approved Family Goals Immune Immune checkpoint inhibitor Immune signaling Immune system Immunoglobulins Immunotherapy Inflammation Inflammatory Lectin Ligand Binding Ligands Malignant Neoplasms Mediating Membrane Glycoproteins Modality Molecular Myeloid Cells Natural Killer Cells Pathology Patients Pattern Polysaccharides Process Proteins Receptor Activation Regulation Relapse Reporter Role SARS-CoV-2 infection Sialic Acids Side Signal Transduction Syndrome T-Lymphocyte Testing Therapeutic Therapeutic Agents Toxic effect Tumor Immunity Tyrosine Virus Diseases Xenograft Model anti-PD-1 anti-cancer base cancer therapy cancer type cell killing cytotoxic cytotoxicity design glycosylation immune activation immune checkpoint immune checkpoint blockade immunological synapse immunoregulation invention macrophage mast cell nanoparticle neoplastic cell novel therapeutics programmed cell death protein 1 receptor receptor binding recruit response sialic acid binding Ig-like lectin tool tumor

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)。