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Analyses of phospholipase A_2 enzymes that are involved in signaling and non-signaling events

参与信号传导和非信号传导事件的磷脂酶 A_2 酶的分析

基本信息

批准号：
14207098
负责人：
KUDO Ichiro
金额：
$ 31.95万
依托单位：
Showa University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2005
项目状态：
已结题

项目摘要

More than 20 phospholipase A_2 (PLA_2) enzymes, which hydrolyze the sn-2 position of glycerophospholipids to liberate fatty acids and lysophospholipids, have been identified in mammals. This study aims to clarify the functions of individual PLA_2 enzymes. In this year, we examined the functions of two secretory PLA_2 (sPLA_2) isozymes in vivo using their transgenic (Tg) and knockout (KO) mice.On the basis of our recent finding that group X sPLA_2 (sPLA_2-X) is located in peripheral neuronal fibers, we herein looked for some neuronal phenotypes in sPLA_2-X KO mice. We found that the pain nociception induced by intraperitoneal administration of acetic acid was significantly reduced in sPLA_2-X KO mice as compared with that in replicate wild-type (WT) mice. Conversely, enhanced pain response was observed in sPLA_2-X Tg mice relative to that in WT mice. Immunohistochemistry revealed that the immunoreactive sPLA_2-X staining was found in the sciatic nerve fibers as well as in dorsal root ga … More nglions adjacent to the spinal cord. We therefore speculate that the neuron-associated sPLA_2-X may play a regulatory role in the neuronal transmission through as yet unknown mechanisms.We found that group III sPLA_2 (sPLA_2-III) Tg mice displayed altered plasma lipoprotein composition manifested by decreased HDL and increased modified LDL levels, an event that is generally believed to be linked to atherosclerosis. The view that sPLA_2-III might be involved in the process of atherosclerosis was further supported by immunohistochemical observation that sPLA_2-III immunoreactivity was found in the atherosclerotic lesions in humans as well as those in apoE-deficicent mice. Moreover, sPLA_2-III Tg mice fed with high-fat diet exhibited obesity relative to replicate WT mice. In addition to these metabolic syndrome-like phenotypes, passive cutaneous anaphylactic reaction was elevated in sPLA_2-III Tg mice relative to replicate WT mice, and splenomegaly and dermatitis occurred spontaneously and progressively in aged sPLA_2-III Tg mice, suggesting unexplored actions of sPLA_2-III on the immune system. Finally, we have succeeded in generating sPLA_2-III-deficient mice, which will unveil the physiological relevance of the aforementioned pathogenic aspects observed in sPLA_2-III Tg mice. Less

磷脂酶A_2（PLA_2）是哺乳动物体内发现的一种水解甘油磷脂的酶，它水解甘油磷脂的sn-2位，释放出脂肪酸和溶血磷脂。本研究旨在阐明PLA_2酶的功能。本研究利用两种分泌型PLA_2（sPLA_2）同功酶的转基因（Tg）和基因敲除（KO）小鼠，研究了它们在体内的功能，并在最近发现X组sPLA_2（sPLA_2-X）定位于外周神经纤维的基础上，对sPLA_2-X KO小鼠的神经元表型进行了研究。我们发现sPLA_2-X基因敲除小鼠腹腔注射醋酸所引起的疼痛伤害性感受较野生型小鼠明显减弱。相反，在sPLA_2-X Tg小鼠中观察到相对于WT小鼠增强的疼痛反应。免疫组化结果显示，sPLA_2-X免疫反应阳性物质主要分布于坐骨神经纤维和背根神经节 ...更多信息与脊髓相邻的神经胶质细胞。我们发现第III组sPLA_2（sPLA_2-III）Tg小鼠血浆脂蛋白组成发生改变，表现为HDL水平降低和修饰LDL水平升高，这一事件通常被认为与动脉粥样硬化有关。免疫组化结果显示，人和apoE缺陷小鼠动脉粥样硬化病变中均有sPLA_2-III的表达，这进一步支持了sPLA_2-III可能参与动脉粥样硬化过程的观点。此外，sPLA_2-III Tg小鼠喂养高脂饮食表现出肥胖相对于复制WT小鼠。除了这些代谢综合征样表型外，sPLA_2-III Tg小鼠的被动皮肤过敏反应相对于复制WT小鼠升高，并且脾肿大和皮炎在老年sPLA_2-III Tg小鼠中自发地和进行性地发生，这表明sPLA_2-III对免疫系统的未探索的作用。最后，我们成功地产生了sPLA_2-III缺陷小鼠，这将揭示上述在sPLA_2-III Tg小鼠中观察到的致病方面的生理相关性。少