Cytoplasmic Lipid Bodies of Inflammatory Cells

炎症细胞的细胞质脂质体

• 批准号: 7764762
• 负责人: PETER F WELLER
• 金额: $ 42.08万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-07-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7764762
• 关键词: Abbreviations; Address; Adipocytes; Agonist; Allergic; Allergic Disease; Allergic inflammation; Antibiotic A23187; Arachidonate 5-Lipoxygenase; Arachidonic Acids; Aspirin; Asthma; Avidin; Basophils; Biotin; Calcium; Cells; Complex; Cytokine Receptors; Cytoplasmic Granules; Cytoplasmic Inclusion; Cytosolic Phospholipase A2; Dinoprostone; Disease; Disseminated eosinophilic collagen disease; Eicosanoids; Endoplasmic Reticulum; Enzymes; Extracellular Signal Regulated Kinases; Glycerol; Hydroxyeicosatetraenoic Acids; IgE; Immunoglobulin binding proteins; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Interleukin-16; Investigation; Ionophores; Leukocytes; Leukotriene B4; Leukotriene C4; Leukotrienes; Lipids; Lipopolysaccharides; Lipoxygenase; Mediating; Mediator of activation protein; Membrane; Messenger RNA; Mitogen-Activated Protein Kinase Kinases; Mitogen-Activated Protein Kinases; Modeling; Monoclonal Antibodies; Nuclear; Oleic Acids; Organelles; P-Glycoproteins; Phospholipase; Platelet Activating Factor; Play; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Protein Biosynthesis; Protein Kinase C; Proteins; Proteome; Proteomics; Public Health; Rattus; Regulation; Renaissance; Research; Ribosomes; Role; Signal Pathway; Signal Transduction; Site; TNF gene; Tetradecanoylphorbol Acetate; Tissues; base; cysteinyl leukotriene receptor; cysteinyl-leukotriene; cytokine; eosinophil; extracellular; human FRAP1 protein; in vivo; interest; leukemia; leukotriene-C4 synthase; mRNA Expression; mTOR protein; mast cell; neutrophil; novel; paracrine; public health relevance; receptor; receptor expression; response

DESCRIPTION (provided by applicant): Lipid bodies are cytoplasmic inclusions that develop in leukocytes, including eosinophils and mast cells, associated with allergic inflammation. Our investigations of the formation and function of leukocyte lipid bodies have revealed that they are distinct, inducible endoplasmic reticulum (ER)-derived, membrane- and ribosome-containing organelles with diverse functional roles in inflammatory responses of leukocytes pertinent to allergic inflammation. Leukocyte lipid bodies contain all enzymes required for synthesizing cyclooxygenase (COX)- and lipoxygenase (LO)-derived eicosanoids. Lipid body formation, rapidly inducible in vitro and in vivo by specific intracellular signaling pathways, enhances leukocyte formation of COX- and LO-derived eicosanoids. Lipid bodies are discrete sites of new eicosanoid synthesis, as documented for immunolocalized LTC4, LTB4 and PGE2. Lipid body-derived eicosanoids function as both paracrine and intracrine mediators of allergic inflammation. Based on combined proteomic and ultrastructural studies, leukocyte lipid bodies are complex organelles with internal membranes and ribosomes whose proteome includes proteins involved in protein synthesis. In IgE-activated cells, lipid bodies are early sites of agonist- elicited 5-LO mRNA localization and de novo 5-LO, LTC4 synthase and cytosolic phospholipase A2 protein synthesis. In addition, lipid bodies are sites of localization of cytokines, including TNF- demonstrable in vivo in tissue and blood leukocytes, although mechanisms and consequences of lipid body cytokine local- ization are unknown. Our central hypothesis is that leukocyte lipid bodies associated with allergic inflammation are inducible organelles that have major roles in the regulated formation of eicosanoids and cytokines that function as intra- and extracellular mediators of allergic inflammation. Our investigations have three aims: 1) Investigate the formation and function of eicosanoids within lipid bodies by evaluating the regulation of eicosanoid- synthesizing enzymes at lipid bodies, including 5-LO regulatory interactions with other proteins in lipid bodies and lipid bodies as sites of differential eicosanoid formation. 2) Investigate the formation and function of cytokines within lipid bodies by studying mechanisms regulating the formation and accumulation of cytokines within leukocyte lipid bodies and whether lipid body localized cytokines function locally within lipid bodies by signaling via cytokine receptors present within lipid bodies. 3) Investigate the mechanisms regulating leukocyte lipid body-related mRNA expression and function. The planned studies aim to provide a better understanding of mechanisms by which leukocytes contribute to inflammation pertinent to allergic and other diseases. PUBLIC HEALTH RELEVANCE: Asthma and related disorders due to allergic inflammation are increasingly prevalent diseases. The research will help in understanding mechanisms of allergic inflammation that are responsible for making asthma and allergic diseases major public health problems.

描述(申请人提供)：脂体是在白细胞中形成的细胞质内含物，包括嗜酸性粒细胞和肥大细胞，与过敏性炎症有关。我们对白细胞脂体的形成和功能的研究表明，它们是独特的、可诱导的内质网(ER)来源的、含有膜和核糖体的细胞器，在与变态反应性炎症相关的白细胞的炎症反应中具有不同的功能。白细胞脂体含有合成环氧合酶(COX)和脂氧合酶(LO)衍生二十烷类化合物所需的所有酶。通过特定的细胞内信号通路在体外和体内快速诱导的脂体形成，促进了COX和LO来源的二十烷基类化合物的白细胞形成。脂体是合成新二十烷类化合物的离散位置，免疫定位的LTC4、LTB4和PGE2都有记录。脂体衍生的二十烷基类化合物既是过敏性炎症的旁分泌介质，也是内分泌介质。基于蛋白质组学和超微结构相结合的研究，白细胞脂体是具有内膜和核糖体的复杂细胞器，其蛋白质组包括参与蛋白质合成的蛋白质。在IgE激活的细胞中，脂体是激动剂诱导的5-LO mRNA定位和5-LO、LTC4合成酶和胞浆磷脂酶A2蛋白合成的早期部位。此外，脂体是细胞因子的定位部位，包括体内可在组织和血白细胞中证明的肿瘤坏死因子，尽管脂体细胞因子局部化的机制和后果尚不清楚。我们的中心假设是，与过敏性炎症相关的白细胞脂体是可诱导的细胞器，在二十烷基类化合物和细胞因子的调节形成中发挥重要作用，这些细胞因子起到过敏性炎症的细胞内外介质的作用。我们的研究有三个目的：1)通过评估脂体中二十烷类合成酶的调节，包括与脂体和脂体中其他蛋白质的5-LO调节相互作用，研究二十烷类化合物在脂体中的形成和功能。2)通过研究细胞因子在白细胞内的形成和积聚的调节机制，以及脂体内细胞因子是否通过脂体内存在的细胞因子受体的信号传递而在脂体内局部发挥作用，来研究细胞因子在脂体内的形成和功能。3)探讨白细胞脂体相关基因表达和功能的调控机制。计划中的研究旨在更好地了解白细胞促进与过敏和其他疾病有关的炎症的机制。公共卫生相关性：哮喘和过敏性炎症引起的相关疾病是日益流行的疾病。这项研究将有助于理解过敏性炎症的机制，这些炎症是导致哮喘和过敏性疾病成为主要公共卫生问题的原因。