Lipid Mediators and Lipid Metaborome

脂质介质和脂质代谢组

• 批准号: 15002004
• 负责人: SHIMIZU Takao
• 金额: $ 443.46万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Specially Promoted Research
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-15002004/
• 关键词: Lipid mediator; Acyltransferase; Platelet-activating factor; Phospholipase A2; G protein-coupled receptor; Knockout mice (or Gene-deficient mice); Metabolome; Pulmonary surfactant lipids; アシル転位酵素; ロイトコイエン; 質量分析計; ロイトコリエン; Gタンパク共役型受容; ロイコトリエン

1 Functional analysis of lysophospholipid acyltransferase ; We identified several lysophospholipid acyltransferases involving in the remodeling pathway of membrane lipids biosynthesis by in silico database analyses. Based on these information, we succeeded in molecular cloning of lyso-PAF acetyltransferase and LPCAT1. Lyso-PAF acetyltransferase is a critical enzyme in stimulus dependent formation of PAR LPCAT1 is an acetyltransferase involving in synthesis of phosphatidylcholine in pulmonary surfactant and play a pivotal role in respiratory physiology. We are generating gene-deficient mice of these enzymes to clarify the physiological importance. We further analyze other enzymes in this family.2 Functional analysis of phospholipase A_2 (PLA_2) ; Among many mammalian PLA_2s, cytosolic PLA_2 α(cPLA_2α) plays a critical role in various physiological and pathophysiological conditions through generating lipid mediators. We newly discovered cPLA_2 family enzymes, cPLA_2δ, cPLA_2ε, and cPLA_2 … More ζ . We are analyzing the physiological function of these enzymes.3 Identification of novel lipid mediator receptors (G-protein coupled receptors : GPCRs) ; To search for novel lipid mediator receptors among approx. 150 orphan GPCRs, we succeeded in selecting approx. 30 candidate GPCRs. In these GPCRs, we have newly identified TDAG8 and G2A as proton-sensing receptors and LPA4 as a lysophosphatidic acid receptor. We are continuously performing the ligand screening for other orphan GPCRs.4 Analysisi of GPCR-deficient mice ; To clarify the physiological significance of lipid mediator GPCRs, we have generated genedeficient mice for BLT1, BLT2, CysLT2 and LPA4. In the analysis of BLT1-deficient mice, we obtained evidence that BLT1 is necessary for production of Th2 cytokines and the development of airway hyperresponsiveness in an OVA-induced bronchial asthma model.5 High throughput quantitation of lipid mediators by LC-MS ; By the combination of lipid chromatography and tandem mass spectrometry (MS/MS), we developed a highly specific and reasonably sensitive assay procedure to simultaneously quantitate > 14 different mediators in 10 min single run. Less

1 溶血磷脂酰基转移酶的功能分析；基于这些信息，我们成功地对溶血磷脂酰基转移酶和LPCAT1进行了分子克隆。 PAR LPCAT1 刺激依赖性形成中的关键酶是一种参与肺表面活性物质中磷脂酰胆碱合成的乙酰转移酶，在呼吸生理学中发挥着关键作用。我们正在培育这些酶的基因缺陷小鼠，以阐明该家族中的其他酶的生理重要性。2 磷脂酶 A_2 的功能分析。 (PLA_2) ; 在许多哺乳动物 PLA_2 中，胞质 PLA_2 α(cPLA_2α) 在多种生理和功能中发挥着关键作用。我们新发现了 cPLA_2 家族酶、cPLA_2δ、cPLA_2ε 和 cPLA_2 … 更多 ❖ 我们正在分析这些酶的生理功能。3 新型脂质介质受体（G 蛋白偶联受体：GPCR）的鉴定。为了在大约 150 个孤儿 GPCR 中寻找新的脂质介质受体，我们成功地选择了大约 1 个。在这些GPCR中，我们新鉴定出TDAG8和G2A作为质子敏感受体，LPA4作为溶血磷脂酸受体。我们正在持续对其他孤儿GPCR进行配体筛选。4 GPCR缺陷小鼠的分析；为了了解脂质介质 GPCR 的生理意义，我们在分析中培育了 BLT1、BLT2、CysLT2 和 LPA4 基因缺陷小鼠。通过对 BLT1 缺陷小鼠进行研究，我们获得了证据，表明 BLT1 对于 OVA 诱导的支气管哮喘模型中 Th2 细胞因子的产生和气道高反应性的发展是必需的。5 通过 LC-MS 对脂质介质进行高通量定量。色谱法和串联质谱法 (MS/MS)，我们开发了一种高度特异性且相当灵敏的测定程序，可在 10 分钟内同时定量 > 14 种不同的介质单次运行较少。

项目成果

Immunomodulation by n-3- vs. n-6-rich lipid emulsions in munne acute lung injury ? role of platelet-activating factor receptor.

富含 n-3 与富含 n-6 的脂肪乳剂对小鼠急性肺损伤的免疫调节作用？

• 发表时间: 2007
• 作者: Schaefer; M. B.; Ott; J.; Mohr; A.; Bi; M. H.; Grosz; A.; Weissmann; N.; Ishii; S.; Grimminger; F.; Seeger; W.; Mayer; K.
• 通讯作者: K.

Profiling of eicosanoid production in the rat hippocampus during kainate-induced seizure : Dual-phase regulation and differential involvement of cox-1 and cox-2.

红藻氨酸诱导的癫痫发作期间大鼠海马类二十烷酸的产生概况：cox-1 和 cox-2 的双相调节和差异参与。

• 发表时间: 2006
• 作者: Yoshikawa; K.; Kita; Y.; Kishimoto; K.; Shimizu; T.
• 通讯作者: T.

Group X secretory phospholipase A2 can induce arachidonic acid release and eicosanoid production without activation of cytosolic phospholipase A2.

X 族分泌型磷脂酶 A2 可以诱导花生四烯酸释放和类二十烷酸产生，而无需激活胞质磷脂酶 A2。

• 发表时间: 2005
• 作者: Saiga; A.; Uozumi; N.; Ono; T.; Seno; K.; Ishimoto; Y.; Arita; H.; Shimizu; T.; Hanasaki; K.
• 通讯作者: K.

G2A is a proton-sensing G-protein coupled receptor antagonized by lysophosphatidylcholine.

G2A 是一种质子感应 G 蛋白偶联受体，可被溶血磷脂酰胆碱拮抗。

• 发表时间: 2004
• 作者: Murakami; N.; Yokomizo; T.; Okuno; T.; Shimizu; T.
• 通讯作者: T.

Rapid and selective identification of molecular species in phosphatidylcholine and sphingomyelin by conditional neutral loss scanning and MS3.

通过条件中性丢失扫描和 MS3 快速、选择性地鉴定磷脂酰胆碱和鞘磷脂中的分子种类。

• 发表时间: 2004
• 作者: Houjou; T; Yamatani; K.; Nakanishi; H.; Imagawa; M.; Shimizu; T.; Taguchi; R.
• 通讯作者: R.