Biochemical Studies of 14-kDa Phospholipases A2

14-kDa 磷脂酶 A2 的生化研究

• 批准号: 9065634
• 负责人: Michael H Gelb
• 金额: $ 42.15万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-12-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9065634
• 关键词: Affinity; Arachidonic Acids; Arthritis; Asthma; Award; Binding; Biochemical; Cells; Disease; Eicosanoids; Enzymes; Extracellular Fluid; Extracellular Space; Extrinsic asthma; Family; Future; Generations; Human; In Vitro; Inflammation; Inflammatory; Instruction; Investigation; Knockout Mice; Lead; Leukotriene Production; Ligands; Lysosomes; Mammals; Mediating; Modeling; Molecular; Mus; Phospholipase A2; Phospholipids; Play; Process; Property; Recombinant Proteins; Role; Testing; Therapeutic; Umbilical Cord Blood; Venoms; Work; airway inflammation; arachidonate; base; cysteinyl-leukotriene; eosinophil; inhibitor/antagonist; lipid mediator; mammalian genome; mouse genome; mouse model; receptor; receptor function; receptor mediated endocytosis

The eicosanoid family of lipid mediators modulates a number of inflammatory processes including ainway inflammation related to asthma. The eicosanoids are biosynthesized from arachidonic acid, which is liberated from the cellular phospholipids by a family of enzymes called phospholipase A2, The mammalian genome encodes 10 secreted phospholipases A2 (sPLA2s), and the role of these enzymes in mediating arachidonic acid release is under active investigation. Cells also contain a cytosolic PLA2 (cPI_A2alpha) that works in a coordinated rnanner with sPLA2s to maximize arachidonic acid release. Recently, we have expressed all of the mouse and human sPLA2s as recombinant proteins and have studied their enzymatic properties in vitro. Mammals also contin an sPI_A2 receptor, the M-type sPLA2 receptor, which was discovered by use of venom sPLA2s. We have shown that many of the mammalian sPLA2s are high affinity ligands for this receptor. The focus of our future studies is to explore the role of high specific activity sPl-A2s in the liberation of arachidonic acid leading to eicosanoids. We will study the molecular basis for the coordinated action of sPLA2s with CPLA2alpha. We will also develop and use tight binding sPLA2 inhibitors to probe the role of these enzymes in arachidonic acid release. We have generated mice that are deficient in human group X spLA2 and have shown that airway inflammation is maredly reduced in a mouse model of allergic asthma in this mouse. We will continue to study the role of group X sPI_A2 in promoting airway inflammation related to asthma. We are also generating mice that are deficient in the other high specific activity sPLA2s and also the M-type sPLA2 receptor. We will also test the possibility that the M-type sPLA2 receptor functions to clear sPLA2s from the extracellular fluid once they have been secreted from cells.

脂质介质的类花生酸家族调节许多炎症过程，包括Ainway 炎症与哮喘有关。类eicosanoids是从花生四烯酸的生物合成的，这是 由称为磷脂酶A2的酶家族从细胞磷脂中释放 基因组编码10个分泌的磷脂酶A2（SPLA2S），这些酶在介导中的作用 花生四烯酸释放正在积极研究中。细胞还包含胞质PLA2（CPI_A2Alpha） 在具有SPLA2S的协调RNANNER中工作，以最大程度地释放花生四烯酸。 最近，我们以重组蛋白表示所有小鼠和人的spla2s 在体外研究了它们的酶特性。哺乳动物还持续SPI_A2受体，M型SPLA2 受体，通过使用毒液spla2s发现。我们已经证明了许多哺乳动物 SPLA2是该受体的高亲和力配体。 我们未来研究的重点是探索高特定活动SPL-A2在解放中的作用 花生四烯酸导致类花生酸酯。我们将研究分子基础的协调作用 带有CPLA2Alpha的SPLA2。我们还将开发和使用紧密的结合SPLA2抑制剂来探测 这些酶在花生四烯酸中释放。 我们已经产生了缺乏人类X spla2的小鼠，并表明气道 在该小鼠的过敏性哮喘的小鼠模型中，炎症会降低。我们将继续 研究X组SPI_A2组在促进与哮喘相关的气道炎症中的作用。我们也是 产生在其他高特异性活动SPLA2和M型SPLA2中不足的小鼠 受体。我们还将测试M型SPLA2受体功能以清除Spla2s的可能性 细胞外流体一旦从细胞中分泌出来。

项目成果

Group X secretory phospholipase A2 regulates the expression of steroidogenic acute regulatory protein (StAR) in mouse adrenal glands.

X 组分泌性磷脂酶 A2 调节小鼠肾上腺中类固醇生成急性调节蛋白 (StAR) 的表达。

• DOI: 10.1074/jbc.m109.090423
• 发表时间: 2010
• 期刊: The Journal of biological chemistry
• 作者: Shridas,Preetha;Bailey,WilliamM;Boyanovsky,BorisB;Oslund,RobC;Gelb,MichaelH;Webb,NancyR
• 通讯作者: Webb,NancyR

Lack of group X secreted phospholipase A₂ increases survival following pandemic H1N1 influenza infection.

• DOI: 10.1016/j.virol.2014.01.030
• 发表时间: 2014-04
• 期刊: VIROLOGY
• 影响因子: 3.7
• 作者: Kelvin, Alyson A.;Degousee, Norbert;Banner, David;Stefanski, Eva;Leon, Alberto J.;Angoulvant, Denis;Paquette, Stephane G.;Huang, Stephen S. H.;Danesh, Ali;Robbins, Clinton S.;Noyan, Hossein;Husain, Mansoor;Lambeau, Gerard;Gelb, Michael;Kelvin, David J.;Rubin, Barry B.
• 通讯作者: Rubin, Barry B.

Study of the role of cytosolic phospholipase A2 alpha in eicosanoid generation and thymocyte maturation in the thymus.

• DOI: 10.1371/journal.pone.0126204
• 发表时间: 2015
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Rousseau M;Naika GS;Perron J;Jacques F;Gelb MH;Boilard E
• 通讯作者: Boilard E

Matrix metalloproteinase-2 negatively regulates cardiac secreted phospholipase A2 to modulate inflammation and fever.

• DOI: 10.1161/jaha.115.001868
• 发表时间: 2015-03-27
• 期刊: Journal of the American Heart Association
• 影响因子: 5.4
• 作者: Berry E;Hernandez-Anzaldo S;Ghomashchi F;Lehner R;Murakami M;Gelb MH;Kassiri Z;Wang X;Fernandez-Patron C
• 通讯作者: Fernandez-Patron C

Epithelial regulation of eicosanoid production in asthma.

• DOI: 10.1016/j.pupt.2012.02.004
• 发表时间: 2012-12
• 期刊: Pulmonary pharmacology & therapeutics
• 影响因子: 3.2
• 作者: Hallstrand TS;Lai Y;Henderson WR Jr;Altemeier WA;Gelb MH
• 通讯作者: Gelb MH