Defining Siglec-6 and Siglec-8 function on effector cells of allergic diseases

定义 Siglec-6 和 Siglec-8 对过敏性疾病效应细胞的功能

基本信息

  • 批准号:
    10097994
  • 负责人:
  • 金额:
    $ 42.29万
  • 依托单位:
  • 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

项目摘要

ABSTRACT In food and drug allergy, anaphylaxis, allergic rhinitis, asthma and other forms of acute and chronic allergic diseases, eosinophils and mast cells, through release of preformed and newly generated mediators, granule proteins, cytokines and other mediators are felt to be key effector cells. Eosinophils and mast cells are also implicated in other type 2 immunologic diseases including chronic rhinosinusitis, eosinophilic esophagitis and atopic dermatitis. For many allergic diseases, drugs that inhibit mast cell degranulation, reduce eosinophil numbers, or counteract their released mediators are useful therapies, but all remain incompletely effective. Siglec-6 and Siglec-8 are members of the CD33-related subfamily of sialic acid-binding immunoglobulin-like lectins (siglecs). Siglec-6 is found on human mast cells, some B cells and cyto- and syncytiotrophoblasts of the placenta, while Siglec-8 is expressed on human eosinophils, mast cells and weakly on basophils. These transmembrane proteins contain N-terminal extracellular lectin binding domains that recognize distinct glycan ligands, and c-terminal intracellular domains including putative ITIM and ITSM signaling motifs. Both Siglec-6 (no mouse counterpart) and Siglec-8 (with Siglec-F being its closest mouse counterpart) preferentially and uniquely recognize specific glycan ligand structures. Engagement of Siglec-8/-F with antibodies or artificial ligands causes eosinophil death. Mice deficient in Siglec-F, or deficient in the airway mucin Muc5b, which carries sialoside ligands for Siglec-F, display exaggerated allergic eosinophilic pulmonary inflammation. Siglec-8 on mast cells, in contrast, does not influence cell survival, but instead functions to inhibit IgE-mediated activation. Less is known about Siglec-6, a prominently expressed human mast cell protein. Available data suggest that Siglec-6 may also function as an inhibitory receptor, and both Siglec-6 and Siglec-8 appear to possess inhibitory activity for both IgE- and non-IgE-mediated mast cell responses. The overall goal of Project 1 is to exploit specific eosinophil and mast cell Siglecs to prevent or treat immediate allergic reactions and chronic allergic inflammation. In particular, Siglec-6 and Siglec-8 provide selective targets for manipulating mast cell and/or eosinophil responses. These concepts will be explored in three specific aims using novel Siglec-6 and Siglec-8 knock-in mice and humanized mice in studies highly integrated with other projects by delineating Siglec-6 and Siglec-8 function and signaling properties in eosinophils and mast cells (Aim 1, with Project 2 and Core B), defining and exploiting Siglec-8 and its ligands for their anti-eosinophil properties in models of chronic eosinophilic inflammation (Aim 2, with Project 2), and exploiting specific ligands of Siglec-6 and Siglec-8 for their anti-mast cell and eosinophil effects (Aim 3, , with Project 2, Project 3 and Core B).
摘要 在食物和药物过敏、过敏性鼻炎、过敏性哮喘和其他形式的急性和慢性过敏 疾病,嗜酸性粒细胞和肥大细胞,通过释放预先形成的和新产生的介质,颗粒 蛋白质、细胞因子和其它介质被认为是关键的效应细胞。嗜酸性粒细胞和肥大细胞也是 与其他2型免疫疾病有关,包括慢性鼻窦炎、嗜酸性食管炎和 特应性皮炎对于许多过敏性疾病,抑制肥大细胞脱颗粒、减少嗜酸性粒细胞 数字,或抵消他们释放的介质是有用的疗法,但都保持不完全有效。 Siglec-6和Siglec-8是唾液酸结合免疫球蛋白样多肽的CD 33相关亚家族的成员。 凝集素(单凝集素)。Siglec-6存在于人肥大细胞、一些B细胞以及人成纤维细胞的细胞滋养层和合体滋养层上。 Siglec-8在胎盘上表达,而Siglec-8在人嗜酸性粒细胞、肥大细胞上表达,在嗜碱性粒细胞上弱表达。这些 跨膜蛋白含有识别不同聚糖的N-末端胞外凝集素结合结构域 配体和C-末端胞内结构域,包括推定的ITIM和ITSM信号传导基序。Siglec-6 (no小鼠对应物)和Siglec-8(Siglec-F是其最接近的小鼠对应物), 唯一识别特定聚糖配体结构。Siglec-8/-F与抗体或人工抗体的接合 配体导致嗜酸性粒细胞死亡。Siglec-F缺陷或气道粘蛋白Muc 5 b缺陷的小鼠, 携带Siglec-F的唾液酸苷配体,显示过度的过敏性嗜酸性肺部炎症。 相比之下,肥大细胞上的Siglec-8不影响细胞存活,而是起到抑制IgE介导的细胞凋亡的作用。 activation.关于Siglec-6,一种显著表达的人类肥大细胞蛋白,知之甚少。可用数据 这表明Siglec-6也可以作为抑制性受体发挥作用,Siglec-6和Siglec-8似乎都 对IgE介导的和非IgE介导的肥大细胞应答都具有抑制活性。项目的总体目标 1是利用特异性嗜酸性粒细胞和肥大细胞Siglecs来预防或治疗即刻过敏反应, 慢性过敏性炎症特别地,Siglec-6和Siglec-8提供了用于操纵的选择性靶标。 肥大细胞和/或嗜酸性粒细胞反应。这些概念将在三个具体的目的,利用小说探讨 Siglec-6和Siglec-8基因敲入小鼠和人源化小鼠的研究与其他项目高度整合, 描述Siglec-6和Siglec-8在嗜酸性粒细胞和肥大细胞中的功能和信号传导特性(Aim 1, 项目2和核心B),定义和利用Siglec-8及其配体在人结肠癌中的抗嗜酸性粒细胞特性。 慢性嗜酸性粒细胞炎症模型(Aim 2,项目2),并利用Siglec-6的特异性配体 和Siglec-8的抗肥大细胞和嗜酸性粒细胞作用(目标3,与项目2、项目3和核心B)。

项目成果

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Bruce S Bochner其他文献

Bruce S Bochner的其他文献

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{{ truncateString('Bruce S Bochner', 18)}}的其他基金

Exploiting Siglec-6 for targeted anti-allergy drug delivery into human mast cells
利用 Siglec-6 将靶向抗过敏药物输送到人体肥大细胞中
  • 批准号:
    10368109
  • 财政年份:
    2021
  • 资助金额:
    $ 42.29万
  • 项目类别:
Exploiting Siglec-6 for targeted anti-allergy drug delivery into human mast cells
利用 Siglec-6 将靶向抗过敏药物输送到人体肥大细胞中
  • 批准号:
    10194041
  • 财政年份:
    2021
  • 资助金额:
    $ 42.29万
  • 项目类别:
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
  • 批准号:
    10331722
  • 财政年份:
    2018
  • 资助金额:
    $ 42.29万
  • 项目类别:
Core A Admin
核心A管理员
  • 批准号:
    10331723
  • 财政年份:
    2018
  • 资助金额:
    $ 42.29万
  • 项目类别:
Core A Admin
核心A管理员
  • 批准号:
    10097991
  • 财政年份:
    2018
  • 资助金额:
    $ 42.29万
  • 项目类别:
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
  • 批准号:
    10097976
  • 财政年份:
    2018
  • 资助金额:
    $ 42.29万
  • 项目类别:
Defining Siglec-6 and Siglec-8 function on effector cells of allergic diseases
定义 Siglec-6 和 Siglec-8 对过敏性疾病效应细胞的功能
  • 批准号:
    10331725
  • 财政年份:
    2018
  • 资助金额:
    $ 42.29万
  • 项目类别:
Human mast cell and tissue acquisition core
人类肥大细胞和组织采集核心
  • 批准号:
    10331724
  • 财政年份:
    2018
  • 资助金额:
    $ 42.29万
  • 项目类别:
Human mast cell and tissue acquisition core
人类肥大细胞和组织采集核心
  • 批准号:
    10097992
  • 财政年份:
    2018
  • 资助金额:
    $ 42.29万
  • 项目类别:
Northwestern University Allergy and Immunology Research (NUAIR) Program
西北大学过敏与免疫学研究 (NUAIR) 项目
  • 批准号:
    10207416
  • 财政年份:
    2010
  • 资助金额:
    $ 42.29万
  • 项目类别:

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阐明皮肤环境因素在过敏性疾病发展中的作用
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