Human Eosinophils: Mechanisms of Functioning

人类嗜酸性粒细胞：功能机制

• 批准号: 7878373
• 负责人: PETER F WELLER
• 金额: $ 1.97万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-15 至 2010-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7878373
• 关键词: ADP-Ribosylation Factors; Abbreviations; Accounting; Acute; Allergic; Antibodies; Arachidonate 5-Lipoxygenase; Arylsulfatase B; Asthma; Biological Assay; Brefeldin A; Cells; Chronic Disease; Cytokine Receptors; Cytoplasmic Granules; Cytoplasmic Vesicles; Detection; Disease; Electron Microscopy; Eosinophil Granule Proteins; Eosinophil cationic protein; Eosinophil-Derived Neurotoxin; Exhibits; Exocytosis; Extracellular Matrix; Globulins; Health; Homeostasis; Human; Hypersensitivity; Immune; Immune system; Inflammation; Interferons; Interleukin-4; Investigation; Leukocytes; Leukotriene C4; Leukotrienes; Ligands; Lipids; Lung; Lymphocyte; Mediating; Methods; Molecular; Monoclonal Antibodies; Pathogenesis; Pertussis Toxin; Phase; Phosphatidylinositols; Phosphotransferases; Platelet Activating Factor; Process; Proteins; RANTES; Research Personnel; Role; Secretory Vesicles; Signal Transduction; Site; Solid; Specificity; Stimulus; Thymus Gland; Tissues; Transport Vesicles; Vesicle; asthmatic airway; base; chemokine; cytokine; eosinophil; eosinophil peroxidase; extracellular; granulocyte; insight; lymph nodes; novel; novel therapeutic intervention; programs; receptor; response; trafficking; vesicle-associated membrane protein

DESCRIPTION (provided by applicant): Eosinophils, cells of the innate immune system, have functions in health and in the pathogeneses of asthma, allergies and other diseases. While some functions of eosinophils are based on their acute, effector responses to release preformed granule cationic proteins, other eosinophil functions are based on their regulated release of diverse cytokines that can mediate interactions with other cells in the microenvironment of tissue sites. Eosinophils function in tissues, especially submucosal sites where eosinophils localize even in the absence of disease. Defining eosinophil cytokine-mediated functional interactions between eosinophils and other cells in tissues is germane to understanding eosinophil functions in both ongoing immune homeostasis and acute and chronic diseases. Amongst leukocytes, eosinophils distinctly contain multiple preformed cytokines stored within morphologically unique granules and secretory vesicles. Eosinophils in tissue sites of inflammation, such as asthmatic airways, exhibit ultrastructural alterations indicative of a specific "piecemeal degranulation" process based on vesicular transport, not exocytosis, that releases, with selectivity, specific proteins from eosinophil granules. In contrast to lymphocytes, cells of the adaptive immune system, a special capacity of eosinophils is their potential to rapidly release preformed cytokines; but mechanisms regulating selective release of eosinophil-derived cytokines remain to be delineated. Studies will investigate mechanisms involved in the regulated release of eosinophil-derived proteins, including cytokines. The overall hypothesis is that, central to the functions of eosinophils, the intracellular compartmentalization, trafficking and release of relevant eosinophil proteins, including cytokines, are dependent on regulatory mechanisms that with stimulus dependent specificity can finely regulate the differential and selective secretion of cytokines. Aims are to define: 1) eosinophil vesicle and granule mechanisms involved in cytokine release; 2) intracellular mechanisms for specificity of eosinophil cytokine release; and 3) stimulus-dependent mobilization and release of eosinophil cytokines. Understanding molecular and cellular mechanisms that regulate the extracellular release of eosinophil-derived cytokines will provide insights into eosinophil functions that involve interactions between eosinophils and other cells in tissue sites in the lung and elsewhere and may identify new therapeutic approaches.

描述（由申请人提供）： 嗜酸性粒细胞是先天免疫系统的细胞，在健康以及哮喘、过敏和其他疾病的发病机制中具有功能。虽然嗜酸性粒细胞的某些功能是基于其对释放预制颗粒阳离子蛋白的急性效应反应，但嗜酸性粒细胞的其他功能是基于其调节释放的多种细胞因子，这些细胞因子可以介导与组织部位微环境中其他细胞的相互作用。嗜酸性粒细胞在组织中发挥作用，尤其是粘膜下位点，即使在没有疾病的情况下，嗜酸性粒细胞也位于其中。定义嗜酸性粒细胞细胞因子介导的嗜酸性粒细胞与组织中其他细胞之间的功能相互作用与了解嗜酸性粒细胞在持续免疫稳态以及急性和慢性疾病中的功能密切相关。在白细胞中，嗜酸性粒细胞明显含有多种预先形成的细胞因子，储存在形态独特的颗粒和分泌囊泡中。炎症组织部位（例如哮喘气道）中的嗜酸性粒细胞表现出超微结构改变，表明基于囊泡运输（而不是胞吐作用）的特定“分段脱颗粒”过程，该过程选择性地从嗜酸性粒细胞颗粒中释放特定蛋白质。与淋巴细胞（适应性免疫系统的细胞）相比，嗜酸性粒细胞的特殊能力是其快速释放预先形成的细胞因子的潜力。但调节嗜酸性粒细胞衍生细胞因子选择性释放的机制仍有待阐明。研究将调查涉及嗜酸性粒细胞衍生蛋白质（包括细胞因子）调节释放的机制。总体假设是，作为嗜酸性粒细胞功能的核心，相关嗜酸性粒细胞蛋白（包括细胞因子）的细胞内区室化、运输和释放依赖于具有刺激依赖性特异性的调节机制，可以精细调节细胞因子的差异性和选择性分泌。目的是明确：1）嗜酸性粒细胞囊泡和颗粒参与细胞因子释放的机制； 2）嗜酸性粒细胞细胞因子释放特异性的细胞内机制； 3) 刺激依赖性嗜酸性粒细胞细胞因子的动员和释放。了解调节嗜酸性粒细胞衍生细胞因子的细胞外释放的分子和细胞机制将有助于深入了解嗜酸性粒细胞的功能，这些功能涉及嗜酸性粒细胞与肺部和其他组织部位的其他细胞之间的相互作用，并可能确定新的治疗方法。

项目成果

Measuring Success in Global Health Training: Data From 14 Years of a Postdoctoral Fellowship in Infectious Diseases and Tropical Medicine.

衡量全球健康培训的成功：传染病和热带医学博士后研究金 14 年的数据。

• 发表时间: 2017-06-15
• 作者: Tucker, Joseph D;Hughes, Molly A;Durvasula, Ravi V;Vinetz, Joseph M;McGovern, Victoria P;Schultz, Rhonda;Dunavan, Claire Panosian;Wilson, Mary E;Milner, Danny A;LaRocque, Regina C;Calderwood, Stephen B;Guerrant, Richard L;Weller, Peter F;Tayl
• 通讯作者: Tayl

Localization of granule proteins in human eosinophil bone marrow progenitors.

颗粒蛋白在人嗜酸性粒细胞骨髓祖细胞中的定位。

• DOI: 10.1159/000237657
• 发表时间: 1997-10-01
• 期刊: International archives of allergy and immunology
• 影响因子: 2.8
• 作者: A. Egesten;J. Calafat;P. Weller;E. Knol;H. Janssen;T. Walz;I. Olsson
• 通讯作者: I. Olsson

Depletion of eosinophil infiltration by anti-IL-5 monoclonal antibody (TRFK-5) accelerates open skin wound epithelial closure.

抗 IL-5 单克隆抗体 (TRFK-5) 消除嗜酸性粒细胞浸润，加速开放性皮肤伤口上皮闭合。

• DOI: 10.1111/j.1464-410x.2012.11553.x
• 发表时间: 1997-09-01
• 期刊: The American journal of pathology
• 作者: James Yang;A. Torio;R. Donoff;G. Gallagher;Robert Egan;P. Weller;David T. W. Wong
• 通讯作者: David T. W. Wong

Human eosinophil adherence to vascular endothelium mediated by binding to vascular cell adhesion molecule 1 and endothelial leukocyte adhesion molecule 1.

人嗜酸性粒细胞通过与血管细胞粘附分子 1 和内皮白细胞粘附分子 1 结合介导对血管内皮的粘附。

• 发表时间: 1991-08-15
• 影响因子: 11.1
• 作者: Weller, P F;Rand, T H;Goelz, S E;Chi;Lobb, R R
• 通讯作者: Lobb, R R

Mepolizumab or Placebo for Eosinophilic Granulomatosis with Polyangiitis.

美泊利单抗或安慰剂治疗嗜酸性肉芽肿性多血管炎。

• 发表时间: 2017-05-18
• 作者: Wechsler, Michael E;Akuthota, Praveen;Jayne, David;Khoury, Paneez;Klion, Amy;Langford, Carol A;Merkel, Peter A;Moosig, Frank;Specks, Ulrich;Cid, Maria C;Luqmani, Raashid;Brown, Judith;Mallett, Stephen;Philipson, Richard;Yancey, Steve W;Stei
• 通讯作者: Stei