The Macromolecular Organization of Leukotriene Synthesis and Renal Inflammation

白三烯合成与肾脏炎症的大分子组织

基本信息

批准号：
8190089
负责人：
Angela Bair Schmider
金额：
$ 15.95万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8190089
关键词：
Acids Acute Affinity Chromatography Allergic rhinitis Amino Acids Arachidonate 5-Lipoxygenase Arachidonic Acids Asthma Atherosclerosis Binding Calcium Cell Culture Techniques Cells Chronic Clinical Research Cobalt Complex Cytosolic Phospholipase A2 Development Disease Dissociation Eicosanoids Enzymes Family Fibrosis G Protein-Coupled Receptor Genes Goals Host Defense Hydrolase IgE Image Immune response Individual Infection Inflammation Inflammatory Injury Kidney Kidney Diseases LTB4R gene Lead Leukocytes Leukotriene A4 Leukotriene B4 Leukotriene B4 Receptors Leukotriene C4 Leukotrienes Ligands Lipids Macromolecular Complexes Mass Spectrum Analysis Mediating Mediator of activation protein Membrane Metabolism Microscopy Molecular Movement Mutation Nuclear Nuclear Envelope Parents Pathogenesis Play Proteins Recruitment Activity Regulation Reperfusion Injury Role Signal Transduction Signaling Molecule Stable Isotope Labeling Testing Tissues Vascular Endothelial Cell chemokine chemokine receptor cysteinyl-leukotriene cytokine interstitial knockout animal leukotriene-C4 synthase mast cell member new therapeutic target novel novel strategies receptor release of sequestered calcium ion into cytoplasm renal ischemia respiratory smooth muscle vascular inflammation

项目摘要

DESCRIPTION (provided by applicant): Leukotrienes (LTs) are members of the eicosanoid family of bioactive signaling molecules derived from the substrate arachdonic acid (AA). LTs are lipid signaling molecules that contribute to the initiation and amplification of the innate and adaptive immune responses. LTs are mediators of asthma and allergic rhinitis, as demonstrated by clinical studies, and studies using knockout animals for the biosynthetic enzymes and receptors. Recently, they have been implicated in the chronic vascular inflammation of atherosclerosis. LTs B4, C4, D4 and E4 function to recruit and activate leukocytes in inflamed tissue, and also regulate the function of endothelial cells, and vascular and airway smooth muscle. The formation of LTC4, the parent cysteinyl LT, requires the functional interaction of at least four proteins on the nuclear envelope. These are cytosolic phospholipase A2 (cPLA2), 5-lipoxygenase (5-LO), the 5- lipoxygenase-activating protein (FLAP), and LTC4 synthase; the metabolism of LTA4 by LTA4 hydrolase (LTA4-H) yields LTB4. Recently, we have shown that 5-LO, FLAP, and LTC4 synthase are assembled in novel macromolecular complexes on the nuclear envelope to initiate LT synthesis. These complexes include an additional FLAP-associated protein, Associated Protein-10 kDa (AP-10), and other proteins. AP-10 dissociates from FLAP concurrent with complex formation, suggesting it has an important regulatory role in LT formation. However, neither its identity nor the signals controlling its dissociation from FLAP are known. The intracellular signals that initiate and sustain the association of 5-LO with FLAP and also the overall assembly of the complex are unknown. One possibility is that sustained intracellular calcium levels are required for both membrane targeting of 5-LO and its association with FLAP. Alternatively, the movement of 5-LO to the nuclear envelope and its incorporation into LT membrane synthetic may be under separate controls. The broad, long-term objective of this proposal is to determine how the assembly of LT membrane synthetic complexes is regulated and to identify each of the components and their roles. PUBLIC HEALTH RELEVANCE: LTs are central to the pathogenesis of asthma and renal disease and inflammation. They are also critical for host defense to infection. The studies proposed in this application will identify novel molecular mechanisms for these diseases and, potentially, novel therapeutic targets.

描述（由申请人提供）：白细胞（LTS）是源自底物蛛网膜酸（AA）的生物活性信号分子的类固醇家族的成员。 LT是脂质信号分子，有助于先天和适应性免疫反应的启动和扩增。如临床研究所证明的那样，LT是哮喘和过敏性鼻炎的介体，以及使用基因敲除动物进行生物合成酶和受体的研究。最近，它们与动脉粥样硬化的慢性血管炎症有关。 LTS B4，C4，D4和E4功能可募集和激活发炎组织中的白细胞，并调节内皮细胞的功能，以及血管和气道平滑肌。 LTC4的形成，母囊藻层LT，需要至少四种蛋白质在核包膜上的功能相互作用。这些是胞质磷脂酶A2（CPLA2），5-脂氧合酶（5-lo），5-脂氧合酶激活蛋白（瓣）和LTC4合酶； LTA4水解酶（LTA4-H）的LTA4代谢产生LTB4。最近，我们表明5-LO，皮瓣和LTC4合酶在核包膜上的新型大分子复合物中组装，以启动LT合成。这些复合物包括额外的皮瓣相关蛋白，相关蛋白-10 kDa（AP-10）和其他蛋白质。 AP-10与同时形成的皮瓣分离，这表明它在LT形成中具有重要的调节作用。但是，它的身份和控制其与皮瓣解离的信号均未知道。启动和维持5-LO与皮瓣以及复合物的整体组装的细胞内信号尚不清楚。一种可能性是，膜靶向5-LO及其与襟翼的关联都需要持续的细胞内钙水平。另外，5-LO向核包膜及其掺入LT膜合成的运动可能在单独的控制下。该提案的广泛长期目标是确定如何调节LT膜合成复合物的组装并确定每个组件及其作用。公共卫生相关性：LTS对于哮喘和肾脏疾病和炎症的发病机理至关重要。它们对于宿主防御感染也至关重要。本应用中提出的研究将确定这些疾病的新型分子机制，并可能是新型的治疗靶标。