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应性炎症中必不可少的效应细胞 应答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）以预防或治疗即刻过敏反应和慢性过敏性炎症。 总体假设是，特异性单克隆抗体、内源性组织聚糖或合成配体类似物可以 特异性和选择性接合互补聚糖结合Siglec（CD 33、Siglec-6和Siglec-8）， 嗜酸性粒细胞和/或肥大细胞，以防止或限制IgE依赖性和IgE非依赖性嗜酸性粒细胞和肥大细胞- 相关过敏反应。 本申请着重于三种肥大细胞和嗜酸性粒细胞Siglecs的作用，我们假设它们提供了 在各种急性和慢性过敏相关疾病中， 紊乱布鲁斯博奇纳博士将担任项目1的主要研究者（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）。James Paulson博士将担任项目2（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（人类 SigleC配体控制肥大细胞和嗜酸性粒细胞介导的炎症）。这是一个项目团队， 生产力和协同作用的跟踪记录。 该应用程序包括检查来自各种来源的Siglec/嗜酸性粒细胞/肥大细胞通路的项目。 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生物学的观点。 生物学，使用体外实验和体内人源化模型。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品，沿着动物模型 涉及人源化肥大细胞小鼠和表达感兴趣的人Siglecs的小鼠的新敲入品系， 提供更深入的机制和结果的假设检验，尚不能评估与 人类研究每个项目都提供了许多新奇的元素，从人类Siglec基因敲入 小鼠开发靶向特异性Siglecs的独特试剂，以发现内源性人类 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.