Using siglecs and their ligands to treat allergic diseases SALTAD

总体摘要 肥大细胞和嗜酸性粒细胞是急性和慢性变态反应性炎症中必不可少的效应细胞 回应。该计划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)，用于预防或治疗即时过敏反应和慢性过敏性炎症。 最重要的假设是，特定的单抗、内源性组织多糖或合成配体类似物可以 特异性和选择性地结合互补的糖链结合Siglecs(CD33、Siglec-6和Siglec-8) 嗜酸性粒细胞和/或肥大细胞，以防止或限制IgE依赖和非IgE依赖的嗜酸性粒细胞和肥大细胞 相关过敏反应。 这个应用着重于我们假设提供的三个肥大细胞和嗜酸性粒细胞标志的作用 抑制各种急慢性变态反应相关变态反应效应细胞反应的理想靶点 精神错乱。Bruce Bochner博士将担任项目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 收购核心)。詹姆斯·保尔森博士将担任项目2的PI(Siglec-靶向纳米颗粒 治疗肥大细胞介导的过敏性疾病)，而罗纳德·施纳尔博士将担任项目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)。这是一个经过验证的计划团队 工作效率和协同效应的跟踪记录。 这个应用程序包括检查Siglec/嗜酸性粒细胞/肥大细胞途径的项目 观点包括药理学、生物化学、细胞信号、糖生物学以及细胞和分子 生物学，采用体外实验和体内人性化模型。大多数拟议的研究 利用人类材料，包括原代人类细胞和生物样本，以及动物模型 涉及人源化肥大细胞小鼠和表达感兴趣的人Siglecs的新敲入小鼠品系 对尚不能评估的机制和结果提供更深入的假设测试 人类研究。每个项目都提供了许多新奇的元素，从人类签名敲门到 小鼠发展独特的靶向特异性Siglecs的试剂来发现内源性人类 特定Siglecs的组织配体。

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.