Using siglecs and their ligands to treat allergic diseases SALTAD

使用siglecs及其配体治疗过敏性疾病SALTAD

基本信息

批准号：
10097976
负责人：
Bruce S Bochner
金额：
$ 151.6万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-02-06 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10097976
关键词：
Acute Allergens Allergic Allergic Disease Allergic Reaction Allergic inflammation Animal Model Asthma Binding Binding Proteins Biochemistry Biological Biopsy Specimen Cells Chronic Development Disease Effector Cell Elements Family Food Functional disorder Gastrointestinal Diseases Gastrointestinal tract structure Glycobiology Goals Health Human Hypersensitivity IgE Immune System Diseases Immunoglobulins In Vitro Inflammation Inflammatory Inflammatory Response Knock-in Knock-in Mouse Knowledge Lectin Ligands Liposomes Mediating Modeling Molecular Molecular and Cellular Biology Monoclonal Antibodies Mouse Strains Mus Outcome Pathway interactions Pharmaceutical Preparations Pharmacology Polysaccharides Productivity Property Reagent Research Role Sampling Sialic Acids Signal Transduction Skin Structure Testing Tissues Translating allergic response analog chronic rhinosinusitis desensitization eosinophil eosinophilic inflammation experience human tissue humanized mouse improved in vivo insight interest mast cell member mouse model nanoparticle novel novel strategies prevent programs response sialic acid binding Ig-like lectin skin disorder synergism

项目摘要

OVERALL ABSTRACT Mast cells and eosinophils are essential effector cells in both acute and chronic allergic inflammatory responses. The overall goal of this Program is to exploit eosinophil and mast cell Siglecs (sialic acid binding, immunoglobulin-like lectins) to prevent or treat immediate allergic reactions and chronic allergic inflammation. The overarching hypothesis is that specific mAbs, endogenous tissue glycans, or synthetic ligand analogs, can specifically and selectively engage complementary glycan binding Siglecs (CD33, Siglec-6, and Siglec-8) on eosinophils and/or mast cells to prevent or limit IgE-dependent and IgE-independent eosinophil and mast cell- related allergic responses. This application focuses on the role of three mast cell and eosinophil Siglecs that we hypothesize provide ideal targets for dampening allergic effector cell responses in a variety of acute and chronic allergy-related disorders. Dr. Bruce Bochner will serve as the PI of Project 1 (Defining Siglec-6 and Siglec-8 function on effector cells of allergic diseases as well as Core A (Administration) and Core B (Human mast cell and tissue acquisition core). Dr. James Paulson will serve as the PI of Project 2 (Siglec-targeted nanoparticles for treating mast cell mediated allergic disease) while Dr. Ronald Schnaar will serve as the PI of Project 3 (Human siglec ligands control mast cell and eosinophil mediated inflammation). This is a Program team with a proven track record of productivity and synergy. This application includes projects that examine Siglec/eosinophil/mast cell pathways from various perspectives including pharmacology, biochemistry, cell signaling, glycobiology, and cellular and molecular biology, using in vitro experimentation and in vivo humanized models. The majority of the proposed research utilizes human material including primary human cells and biologic samples, along with animal models involving humanized mast cell mice and novel knock-in strains of mice expressing human Siglecs of interest to provide more in-depth hypothesis testing on mechanisms and outcomes that cannot yet be assessed with human research. Each Project provides numerous elements of novelty ranging from human Siglec knock-in mice to development of unique reagents for targeting specific Siglecs to discovery of endogenous human tissue ligands for specific Siglecs.

总体抽象肥大细胞和嗜酸性粒细胞是急性和慢性过敏性炎症中必不可少的效应细胞回答。该程序的总体目标是利用嗜酸性粒细胞和肥大细胞siglecs（唾液酸结合，免疫球蛋白样凝集素）可预防或治疗立即的过敏反应和慢性过敏性炎症。总体假设是特定的mAb，内源性组织聚糖或合成配体类似物可以具体，有选择地参与互补的聚糖结合Siglecs（CD33，Siglec-6和Siglec-8）嗜酸性粒细胞和/或肥大细胞，以预防或限制IgE依赖性和IgE非依赖性嗜酸性粒细胞和肥大细胞相关的过敏反应。该应用集中于我们假设提供的三个肥大细胞和嗜酸性粒细胞siglecs的作用在多种急性和慢性过敏有关疾病。 Bruce Bochner博士将作为项目1的PI（定义SIGLEC-6和SIGLEC-8功能过敏性疾病的效应细胞以及核心A（给药）和核心B（人肥大细胞和组织获取核心）。詹姆斯·鲍尔森（James Paulson）博士将担任项目2的PI（SIGLEC靶向的纳米颗粒治疗肥大细胞介导的过敏性疾病），而罗纳德·施纳（Ronald Schnaar）博士将作为项目3的PI（人类 Siglec配体控制肥大细胞和嗜酸性粒细胞介导的炎症）。这是一个计划团队生产力和协同作用的记录。该应用程序包括检查Siglec/嗜酸性粒细胞/肥大细胞途径的项目包括药理学，生物化学，细胞信号传导，糖生物学以及细胞和分子的观点生物学，使用体外实验和体内人性化模型。大多数拟议的研究利用包括原代人细胞和生物样品在内的人类材料以及动物模型涉及人性化的肥大细胞小鼠和表达人类感兴趣的人的新型小鼠菌株提供有关尚无法评估的机制和结果的更深入的假设检验人类研究。每个项目都提供了许多新颖的要素，包括人类的Siglec敲门小鼠开发独特的试剂，以靶向特定的siglecs发现内源性人特定siglecs的组织配体。