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和哮喘，过敏和其他疾病的发病机制中起作用。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它们已经合成的多种 细胞因子与颗粒阳离子蛋白一起沿着储存在嗜酸性粒细胞胞质颗粒和囊泡内。 嗜酸性粒细胞分泌的阳离子和细胞因子介导的嗜酸性粒细胞之间的功能相互作用 蛋白质和组织中的其他细胞与理解嗜酸性粒细胞在两种正在进行的免疫反应中的功能密切相关。 体内平衡和急性和慢性疾病。组织部位的嗜酸性粒细胞表现出 两种形式的“脱颗粒“：1）颗粒内容物通过其被移动到 由细胞质分泌囊泡分泌，和2）通过细胞溶解从 在嗜酸性粒细胞中。我们确定无细胞嗜酸性粒细胞颗粒表达配体结合细胞因子， 类花生酸受体，激活颗粒内信号传导以刺激颗粒分泌。两种激动剂- 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物可以 选择性和差异性地释放阳离子蛋白质和储存在细胞内的许多细胞因子中的一些。 颗粒。研究将调查涉及嗜酸性粒细胞衍生的调节释放的机制。 蛋白质，包括细胞因子和阳离子蛋白质。总的假设是， 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 从嗜酸性粒细胞和它们的游离颗粒依赖于调节机制， 依赖性特异性可以精细地调节细胞因子的差异性和选择性分泌。我们的目标将 探讨：1）调节嗜酸性粒细胞分泌能力的机制; 2） 介导细胞因子和其他蛋白质从嗜酸性粒细胞内分泌的机制;和3） 刺激依赖性动员和嗜酸性细胞因子的靶向释放。了解分子和 调节嗜酸性粒细胞颗粒衍生蛋白的细胞外释放的细胞机制将提供 深入了解嗜酸性粒细胞的功能，涉及嗜酸性粒细胞和其他细胞之间的相互作用。 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， 这些疾病可能导致这些疾病的改进的疗法。