Gene expression analysis of febrile neurons expressing prostaglandin receptor EPS

本研究的目的是(1)了解EP3信号在下丘脑神经元中激活的基因，(2)研究EPS在不同细胞类型中的信号转导机制，(3)阐明哪种EP亚型参与PGE2的具体病理生理作用。(1)为了表征下丘脑EP3阳性神经元的单细胞基因表达谱，我们建立并优化了单细胞基因表达分析方法。通过这种方法，我们研究了PGE2处理后基因表达水平的变化。PGE2降低了包括GABAA受体在内的各种基因的表达水平。应该指出的是，据报道，一种GABA激动剂可以阻断PGE2诱导的发热反应。我们认为GABA受体的下调可能是EP3表达的神经元引起发热的一个关键事件(2)我们发现免疫、卵巢、表皮和粘膜组织中特异性的EP基因表达在不同的KIN…上表达上调更多的DS的刺激(3)EP3已被证明与胃肠道活性偶联，腺苷环化酶的抑制。我们发现，在COS-7细胞中表达的EP3受体以激动剂依赖的方式表现出其他受体刺激的Gs活性的增强。EP3信号可能反映了PGE2生理功能的某些方面，如痛觉(4)我们发现EP2缺乏可以减少APC KO小鼠肠息肉形成的数量和大小。将葡聚糖硫酸盐(DSS)诱导的小鼠结肠炎模型引入EPG小鼠体内。结果，只有EP-4基因缺陷的小鼠在3%DSS治疗后表现出严重的结肠炎，而泰国没有在野生型小鼠中引起明显的结肠炎。EP4已被证明可以促进上皮再生，抑制白细胞和淋巴细胞的激活。我们进一步发现，与野生型小鼠相比，EP3缺陷小鼠的出血倾向增加，对花生四烯酸诱导的血栓栓塞症的易感性降低。EP3通过增加细胞内钙离子和/或降低cAMP水平来增强TP诱导的血小板聚集

The purpose of this study is (1) to understand what genes are activated upon EP3 signaling in hypothalamic neurons, (2) to investigate signal transduction machanisms exerted by EPS in various cell types, and (3) to clarify which EP subtype is involved in particular pathophysiological actions of PGE2(1) In order to characterize single cell gene expression profiles of hypothalamic EP3-positive neurons, we established and optimized single cell gene expression analysis method. By using this method, we characterized genes changes their expression levels upon PGE2 treatment. PGE2 reduced expression levels of various kinds of genes including GABA A receptors. It should be noted that a GABA agonist has been reported to block PGE2-induced febrile response. We proposed that down-regulation of GABA receptor might be a key event in EP3-expressiong neurons to elicit fever(2) We identified upregulation of specific EP gene expression in immune, ovarian, epidermal, and mucosal tissues upon various kin … More ds of stimuli(3) EP3 has been shown to be coupled to Gi activity, inhibition of adenylate cyclase. We found that EP3 receptors expressed in COS-7 cells showed augmentation of other receptor-stimulated Gs activity in an agonistdependent manner. This EP3 signaling may reflect some aspects of the physiological function of PGE2, such as pain sensation(4) We found that EP2 deficiency attenuated intestinal polyp formation both in number and size in Apc KO mice. We introduced dextransulfate (DSS)induced colitis model into Epdeficient mice. As a result, only EP-4deficient mice showed severe colitis upon 3%DSS treatment thai did not induce significant colitisin wild-type mice. EP4 has been shown to promote epithelial regeneration and to inhibit activation of leukocytes and lymphocytes. We further found that EP3-deficient mice showed increased bleeding tendency and decreased susceptibility to arachidonateinduced thromboembolism compared with wild-type mice. EP3 appears to potentiate TP-induced platelet aggregation by increasing intracellular Ca2+ and/or decreasing cAMP level Less