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：
10417251
负责人：
Peng Wu
金额：
$ 79.59万
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/10417251
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).

项目概要/摘要免疫系统的调节很大程度上受到细胞表面聚糖调节的影响。配体-受体结合并设置启动免疫细胞激活下游信号传导的阈值。 Siglecs（唾液酸结合免疫球蛋白型凝集素）是参与这些过程的调节受体家族 Siglec 可以结合在相同或不同表达的顺式和反式唾液酸化聚糖配体。 Siglecs 与其配体的结合可以将 Siglecs 与细胞分开。激活受体或将它们移近抑制性 Siglecs 调节激活受体的能力是。受空间邻近性调节：将 Siglecs 招募到激活受体附近的免疫突触会触发抑制信号来抑制移动的免疫系统激活，而 Siglecs 则远离激活受体将通过激活受体实现最佳信号传导。由于上述原因，最近 Siglecs 被描述为糖免疫检查点。它们与肿瘤细胞上异常表达的唾液酸化聚糖的相互作用，先天免疫细胞相关 Siglecs 触发信号级联反应抑制免疫系统激活，Siglecs 在肿瘤上表达上调。细胞与尚未鉴定的 T 细胞膜糖蛋白相互作用，抑制 T 细胞的抗肿瘤功能。然而，从积极的一面来看，Siglecs 的抑制信号传导可以抑制细胞死亡过程中的炎症尽管有这些有趣的观察结果，但上述机制仍然存在。过程才刚刚开始被阐明。该项目的总体目标是结合使用化学酶、生物化学和探索 Siglec-聚糖配体相互作用及其治疗意义的遗传工具在目标 1 中，我们将。 In Aim 设计基于 Siglec 的嵌合开关受体，并将抑制性 Siglec 转化为激活受体。 2、我们将使用基于细胞的聚糖阵列平台来筛选Siglecs的高亲和力和特异性配体。确定后，我们将探索它们抑制或利用抑制性 Siglec 信号传导进行治疗的效用最后，我们将使用我们的化学酶工具来研究 Siglec-cis 配体如何相互作用。参与介导 Siglec-反式配体相互作用以及相应的免疫细胞激活（目标 3）。