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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

基本信息

批准号：
10799053
负责人：
Peng Wu
金额：
$ 14.61万
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：
2021-02-01 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10799053
关键词：
Affinity Autoimmune Diseases Binding Binding Proteins Biological Process Cell Communication Cell physiology Cell surface Cells Development Disease Progression Engineering Environment FDA approved Fucose Genome Glycoconjugates Glycoproteins Goals Immune Immune System Diseases Immune checkpoint inhibitor Immune signaling Immunoglobulins Immunotherapy In Situ Label Lectin Ligands Malignant Neoplasms Mediating Metabolic Methods Modality Modification Molecular Molecular Biology Techniques Monosaccharides N-acetyllactosamine Natural Killer Cells Oligosaccharides Organism Patients Polysaccharides Production Proliferating Property Recombinants Role Sialic Acids Signal Transduction Specificity Structure T-Lymphocyte Therapeutic Agents Tumor Immunity Vaccination Visualization anti-CTLA4 anti-PD-1 checkpoint inhibition cytokine cytotoxic exhaustion glycosylation glycosyltransferase human disease immune activation immunoregulation interest novel novel therapeutics receptor receptor binding response sialic acid binding Ig-like lectin sialylation sugar nucleotide tool

项目摘要

PROJECT SUMMARY/ABSTRACT Cell-surface glycans participate in numerous biological processes, including signal transduction, cell-cell communication and development. Aberrant glycosylation is a hallmark of human disease. At a molecular level, glycans represent the first points of contact between cells. However, not directly encoded in the genome, these biomolecules are challenging to study using molecular biology techniques alone. Metabolic oligosaccharide engineering (MOE) developed in late 1990’s has revolutionized the way for the labeling and visualization of glycans in living organisms. In this method, cells’ own glycan biosynthetic machinery is hijacked to incorporate unnatural monosaccharides with linkage promiscuity. Complementary to MOE, chemoenzymatic glycan editing has emerged as a valuable tool to probe and modify glycan structures within a cellular environment. Unlike MOE, chemoenzymatic glycan modification utilizes recombinant glycosyltransferases to transfer natural or unnatural monosaccharides with novel functions from activated nucleotide sugars to glycoconjugates on the cell surface with linkage specificity. For these reasons, chemoenzymatic glycan modification provides a facile and more precise way for probing the function of glycans in their native environments. Building upon our successful application of chemoenzymatic glycan editing, in the next five years we will expand our chemoenzymatic tool kits to study glycans’ cellular functions with a focus on the special roles of N- acetyllactosamine (LacNAc), fucose and sialic acid in immune regulation. Cell-surface LacNAc mediates ligand-receptor binding and sets a threshold for initiating the downstream signaling for immune cell activation. LacNAc residues are dynamically modified by sialic acid and/or fucose. However, the specific roles of these modifications in immune regulation and disease progression remain obscure. We are particularly interested in finding out: (1) if changes in LacNAc and fucosylation status can serve as glycan signatures of T cell exhaustion during which T cells gradually lose their cytokine production, proliferation and cytotoxic capacity; (2) Can cell-surface in situ LacNAc fucosylation be used to boost the efficacy of antitumor immunity of T cells and NK cells? In parallel, we will develop chemoenzymatic tools for profiling sialylated glycoprotein ligands of Siglecs (sialic acid-binding immunoglobulin-type lectins) and for the identification of unnatural, high-affinity and specific ligands to interrogate Siglec functions. Through these studies, we will gain a deeper understanding of how LacNAc, fucose and sialic acid are involved in the regulation of the immune cell activation, effector function and exhaustion. Tools developed in this project can also be used to study other types of glycans and their interactions with glycan binding proteins.

项目总结/文摘