CELLULAR REGULATION OF PROSTAGLANDIN SYNTHESIS

描述（改编自研究者摘要）：这是一项竞争性研究， 延长赠款，该赠款几年来一直审查 前列腺素内过氧化物合酶（PGHS）的调节。肾小球系膜 GMC在几种肾小球疾病的发生中起关键作用， 如肾小球硬化和增生性肾小球肾炎， 其特征在于GMC损伤和增殖。促炎剂可以 诱导类二十烷酸细胞合成，即 花生四烯酸，可调节GMC基质合成和增殖。 本申请研究了调节细胞内信号传导机制， PGHS的表达和作用，它催化前列腺素的产生， 花生四烯酸PGHS是特别感兴趣的，是主要目标， NSAIDS。将使用体外和体内研究的组合来测试 PGHS-2表达受丝裂原活化蛋白调节假说 PGHS-2的过度表达具有抗凋亡作用 通过差异基因表达介导。 提出了三个具体目标。具体目标1将评估 假设MAPKs的激活代表了 不同的刺激PGHS-2表达，这是负调控 双特异性磷酸酶。在此，我们观察了注射后对PGHS-2表达的影响。 腺病毒介导的编码野生型和突变型ERK、JNK的基因的转移 和p38 MAPK，以及双特异性磷酸酶将在肾脏中进行研究。 细胞具体目标2将检验PGHS-2表达导致 对几种细胞类型的抗凋亡作用。在这里， 腺病毒介导的PGHS-2基因转染对原代细胞凋亡的影响 将研究参数。抗凋亡作用的机制将是 通过使用cDNA鉴定受PGHS-2表达控制的基因进行研究 微阵列在特异性目标3中，PGHS-2表达和 将使用两种大鼠模型评估与MAPK级联的关系。 肾小球肾炎（GN）。在这里，PGHS-2的表达和前列腺素的产生 将在大鼠肾小球中进行评估，并与MAPK活化和 在疾病的规定时间点的GN的组织病理学。

DESCRIPTION (Adapted from Investigator's Abstract): This is a competitive renewal of a grant, which has for several years examined the mechanisms of regulation of prostaglandin endoperoxide synthase (PGHS). Glomerular mesangial cells (GMC) play a key role in the genesis of several glomerular diseases such as glomerulosclerosis and proliferative glomerulonephritis, which are characterized by GMC injury and proliferation. Proinflammatory agents can induce cellular synthesis of eicosanoids, namely oxygenated products of arachidonic acid, that can regulate GMC matrix synthesis and proliferation. This application examines the intracellular signaling mechanisms regulating the expression and actions of PGHS, which catalyses prostaglandin production from arachidonic acid. PGHS is of particular interest, being the principal target of NSAIDS. A combination of in vitro and in vivo studies will be used to test the hypothesis that PGHS-2 expression is regulated by mitogen activated protein kinases (MAPKs), and that over expression of PGHS-2 has anti-apoptotic effects mediated through differential gene expression. Three Specific Aims have been outlined. Specific Aim 1 will evaluate the hypothesis that activation of MAPKs represents the convergence point of divergent stimuli of PGHS-2 expression, and this is negatively regulated by dual-specificity phosphatases. Here, the effects on PGHS-2 expression after adenovirus mediated transfer of genes encoding wild type and mutant ERK, JNK and p38 MAPKs, and dual-specificity phosphatases will be studied in kidney cells. Specific Aim 2 will examine the hypothesis that PGHS-2 expression leads to anti-apoptotic effects in several cell types. Here the effect of adenovirus-mediated transfer of PGHS-2 gene into primary cells on apoptotic parameters will be studied. The mechanism of the anti-apoptotic effect will be studied by identifying genes controlled by PGHS-2 expression using cDNA micro-arrays. In Specific Aim 3, the in vivo relevance of PGHS-2 expression and relation to the MAPK cascade will be evaluated using two rat models of glomerulonephritis (GN). Here, PGHS-2 expression and prostaglandin production will be assessed in rat glomeruli and correlated with MAPK activation and the histopathology of GN at defined time points of the disease.