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Principal Investigator: Peng Wu
Organization: SCRIPPS RESEARCH INSTITUTE, THE
Fiscal Year: 2024
Award: $809,851
Funding agency: National Institute of Allergy and Infectious Diseases
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).
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><Advanced Cancer><Advanced Malignant Neoplasm><Affinity><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Antigenic Determinants><Binding><Binding Determinants><Binding Proteins><Biochemical><CD152><CD152 Antigen><CD152 Gene><COVID-19 infection><COVID-19 virus><COVID-19 virus infection><COVID19 infection><COVID19 virus><CTLA 4><CTLA-4 Gene><CTLA4><CTLA4 gene><CTLA4-TM><Cancer Patient><Cancer Treatment><Cancers><Cell Body><Cell Communication><Cell Communication and Signaling><Cell Death Induction><Cell Interaction><Cell Line><Cell Signaling><Cell Surface Glycoproteins><Cell surface><Cell-to-Cell Interaction><CellLine><Cells><Checkpoint inhibitor><Clinical><Clinical Trials><CoV-2><CoV2><Cytotoxic T-Lymphocyte Protein 4><Cytotoxic T-Lymphocyte-Associated Antigen 4><Cytotoxic T-Lymphocyte-Associated Protein 4><Cytotoxic T-Lymphocyte-Associated Serine Esterase-4><Cytotoxic cell><Development><Elements><Endowment><Engineering><Epitopes><FDA approved><Family><Genetic><Glycans><Goals><Immune><Immune Cell Activation><Immune Globulins><Immune checkpoint inhibitor><Immune mediated therapy><Immune signaling><Immune system><Immunes><Immunoglobulins><Immunologically Directed Therapy><Immunomodulation><Immunotherapy><Inflammation><Inflammatory><Intracellular Communication and Signaling><K lymphocyte><Lectin><Ligand Binding><Ligand Binding Protein><Ligand Binding Protein Gene><Ligands><Lytotoxicity><Macrophage><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Marrow Mast Cell><Mediating><Membrane Glycoproteins><Metabolic Glycosylation><Modality><Molecular><Molecular Interaction><Myeloid Cells><Mφ><N-Acetylneuraminic Acids><NK Cells><Natural Killer Cells><PD 1><PD-1><PD1><Pathology><Patients><Pattern><Polysaccharides><Process><Protein Binding><Proteins><Receptor Activation><Receptor Protein><Regulation><Relapse><Reporter><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 infection><SARS-CoV2><SARS-CoV2 infection><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome related corona virus 2><Sialic Acids><Side><Signal Transduction><Signal Transduction Systems><Signaling><Strains Cell Lines><Surface Glycoproteins><Syndrome><T-Cells><T-Lymphocyte><Testing><Therapeutic><Therapeutic Agents><Tissue Basophils><Toxic effect><Toxicities><Tumor Cell><Tumor Immunity><Tyrosine><Viral Diseases><Virus Diseases><Wuhan coronavirus><Xenograft Model><aPD-1><aPD1><anti programmed cell death 1><anti-PD-1><anti-PD1><anti-cancer><anti-cancer therapy><anti-programmed cell death protein 1><anti-tumor immunity><antiPD-1><antiPD1><antitumor immunity><biological signal transduction><bound protein><cancer immunity><cancer therapy><cancer type><cancer-directed therapy><cell killing><check point blockade><checkpoint blockade><coronavirus disease 2019 infection><coronavirus disease 2019 virus><coronavirus disease-19 virus><cultured cell line><cytotoxic><cytotoxic T-lymphocyte antigen 4><cytotoxicity><design><designing><developmental><glycosylation><hCoV19><immune activation><immune check point><immune check point blockade><immune check point inhibitor><immune checkpoint><immune checkpoint blockade><immune modulation><immune regulation><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immunecheckpoint><immuno therapy><immunologic reactivity control><immunological synapse><immunomodulatory><immunoregulation><immunoregulatory><infected with COVID-19><infected with COVID19><infected with SARS-CoV-2><infected with SARS-CoV2><infected with coronavirus disease 2019><infected with severe acute respiratory syndrome coronavirus 2><invention><malignancy><mast cell><mastocyte><nCoV2><nano particle><nano-sized particle><nanoparticle><nanosized particle><neoplasm/cancer><neoplastic cell><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><programmed cell death 1><programmed cell death protein 1><programmed death 1><receptor><receptor binding><receptor bound><recruit><response><restraint><segregation><sialic acid binding Ig-like lectin><sialylation><siglec><sle2><social role><systemic lupus erythematosus susceptibility 2><thymus derived lymphocyte><tool><tumor><viral infection><virus infection><virus-induced disease><xenograft transplant model><xenotransplant model><αPD-1><αPD1>