Human Eosinophils: Mechanisms of Functioning

人类嗜酸性粒细胞：功能机制

• 批准号: 9242550
• 负责人: PETER F WELLER
• 金额: $ 53.36万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9242550
• 关键词: Acute Disease; Agonist; Asthma; Cations; Cells; Chronic Disease; Competence; Cytokine Receptor Binding; Cytolysis; Cytoplasmic Granules; Cytoplasmic Vesicles; Disease; Eicosanoid Receptor; Exhibits; Health; Homeostasis; Human; Hypersensitivity; Immune; Innate Immune System; Instruction; Lead; Ligand Binding; Mediating; Molecular; Proteins; Public Health; Secretory Vesicles; Signal Transduction; Site; Specificity; Stimulus; Tissues; cytokine; eosinophil; extracellular; improved; insight; trafficking

Eosinophils function in health and in the pathogeneses of asthma, allergies and other diseases. As cells of the innate immune system, a distinct attribute of eosinophils is their content of multiple already synthesized cytokines stored, along with granule cationic proteins, within eosinophil cytoplasmic granules and vesicles. Defining functional interactions between eosinophils, mediated by their secreted cationic and cytokine proteins, and other cells in tissues is germane to understanding eosinophil functions in both ongoing immune homeostasis and acute and chronic diseases. Eosinophils in tissue sites exhibit ultrastructural evidence of two forms of "degranulation:" 1) piecemeal degranulation by which granule contents are mobilized into and secreted by cytoplasmic secretory vesicles, and 2) release of intact granules extruded by cytolysis from within eosinophils. We established that cell-free eosinophil granules express ligand-binding cytokine and eicosanoid receptors that activate intragranular signaling to stimulate secetion from granules. Both agonist- specific piecemeal degranulation from within intact eosinophils and secretion from within free granules can release, selectively and differentially, cationic proteins and some of the many cytokines stored within granules. Studies will investigate mechanisms involved in the regulated release of eosinophil-derived proteins, including cytokines and cationic proteins. The overall hypothesis is that, central to the functions of eosinophils, the intracellular compartmentalization, trafficking and release of relevant eosinophil proteins from eosinophils and their free granules are dependent on regulatory mechanisms that with stimulus- dependent specificity can finely regulate the differential and selective secretion of cytokines. Our Aims will investigate: 1) mechanisms regulating the secretion competence of cell-free eosinophil granules; 2) mechanisms mediating the secretion of cytokines and other proteins from within eosinophils; and 3) stimulus-dependent mobilization and targeted release of eosinophil cytokines. Understanding molecular and cellular mechanisms that regulate the extracellular release of eosinophil granule-derived proteins will provide insights into eosinophil functions that involve interactions between esosinophils and other cells. RELEVANCE (See instructions): Eosinophil-associated diseases, including asthma, allergies and other disorders, are increasingly prevalent diseases and major public health problems. Better understanding of the functions of eosinophils in these diseases may lead to improved therapies for these diseases.

嗜酸性粒细胞在健康以及哮喘、过敏和其他疾病的发病机制中发挥作用。作为细胞 在先天免疫系统中，嗜酸性粒细胞的一个独特属性是其多种已合成的物质的含量 细胞因子与颗粒阳离子蛋白一起储存在嗜酸性粒细胞胞质颗粒和囊泡内。 定义嗜酸性粒细胞之间由其分泌的阳离子和细胞因子介导的功能相互作用 蛋白质和组织中的其他细胞与了解嗜酸性粒细胞在持续免疫中的功能密切相关 体内平衡以及急性和慢性疾病。组织部位的嗜酸性粒细胞表现出超微结构证据 “脱粒”的两种形式： 1) 分段脱粒，其中颗粒内容物被动员到和 由细胞质分泌囊泡分泌，以及2)通过细胞溶解作用挤出的完整颗粒的释放 嗜酸性粒细胞内。我们确定无细胞嗜酸性粒细胞表达配体结合细胞因子并且 类二十烷酸受体激活颗粒内信号传导以刺激颗粒分离。两者均激动剂- 完整嗜酸性粒细胞内的特定碎片脱颗粒和游离颗粒内的分泌可以 选择性地和差异性地释放阳离子蛋白和储存在其中的许多细胞因子中的一些 颗粒。研究将调查嗜酸性粒细胞衍生的调节释放所涉及的机制 蛋白质，包括细胞因子和阳离子蛋白。总体假设是， 嗜酸性粒细胞，相关嗜酸性粒细胞蛋白的细胞内区室化、运输和释放 嗜酸性粒细胞及其游离颗粒的释放依赖于刺激的调节机制 依赖性特异性可以精细调节细胞因子的差异性和选择性分泌。我们的目标将 研究：1）调节游离嗜酸性粒细胞颗粒分泌能力的机制； 2） 介导嗜酸性粒细胞内细胞因子和其他蛋白质分泌的机制；和 3) 刺激依赖性动员和嗜酸性粒细胞细胞因子的靶向释放。了解分子和 调节嗜酸性粒细胞衍生蛋白的细胞外释放的细胞机制将提供 深入了解涉及嗜酸性粒细胞与其他细胞之间相互作用的嗜酸性粒细胞功能。 相关性（参见说明）： 嗜酸性粒细胞相关疾病，包括哮喘、过敏和其他疾病，越来越普遍 疾病和重大公共卫生问题。更好地了解嗜酸性粒细胞在这些疾病中的功能 疾病可能会导致这些疾病的治疗方法得到改进。