Cytoplasmic Lipid Bodies of Inflammatory Cells

炎症细胞的细胞质脂质体

• 批准号: 7651784
• 负责人: PETER F WELLER
• 金额: $ 42.5万
• 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/7651784
• 关键词: Abbreviations; Address; Adipocytes; Agonist; Allergic; 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; Extrinsic asthma; 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（由申请方提供）：脂质体是在白细胞（包括嗜酸性粒细胞和肥大细胞）中形成的细胞质内含物，与过敏性炎症相关。我们的白细胞脂质体的形成和功能的调查表明，他们是不同的，诱导型内质网（ER）衍生的，膜和核糖体含有细胞器与不同的功能作用的白细胞相关的过敏性炎症的炎症反应。白细胞脂质体含有合成环氧合酶（考克斯）和脂氧合酶（LO）衍生的类二十烷酸所需的所有酶。脂质体的形成，在体外和体内通过特定的细胞内信号传导途径快速诱导，增强白细胞形成的考克斯-和LO-衍生类花生酸。脂质体是新类花生酸合成的离散位点，如免疫定位的LTC 4、LTB 4和PGE 2所记录的。脂质体衍生的类二十烷酸作为过敏性炎症的旁分泌和内分泌介质发挥作用。基于结合蛋白质组学和超微结构的研究，白细胞脂质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，脂质体是激动剂诱导的5-LO mRNA定位和从头5-LO、LTC 4合酶和胞质磷脂酶A2蛋白合成的早期位点。此外，脂质体是细胞因子的定位位点，包括在体内组织和血液白细胞中可证实的TNF-α，尽管脂质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质体是可诱导的细胞器，在调节类花生酸和细胞因子的形成中起主要作用，类花生酸和细胞因子作为过敏性炎症的细胞内和细胞外介质。我们的研究有三个目的：1）通过评价脂体中类花生酸合成酶的调节，包括5-LO与脂体中其他蛋白质的相互作用以及脂体作为类花生酸差异形成位点的调节，来研究脂体中类花生酸的形成和功能。2)通过研究调节白细胞脂质体内细胞因子的形成和积累的机制，以及脂质体内定位的细胞因子是否通过脂质体内存在的细胞因子受体进行信号传导，在脂质体内局部发挥作用，研究脂质体内细胞因子的形成和功能。3)探讨调节白细胞脂质体相关mRNA表达和功能的机制。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相关的炎症的机制。公共卫生相关性：过敏性炎症引起的哮喘和相关疾病越来越普遍。这项研究将有助于了解过敏性炎症的机制，这些机制是导致哮喘和过敏性疾病成为主要公共卫生问题的原因。