REGULATION OF LIPID AUTOCOIDS IN CARDIOVASCULAR CELLS

这个项目的目标是了解如何生产的 类二十烷酸（类花生四烯酸和白三烯）和血小板- 活化因子在几种相关细胞中受到调节， 心血管疾病 类二十烷酸是含氧代谢物 花生四烯酸，具有不同的，有效的影响， 病理生理过程 它们由心脏细胞产生 （包括心包、心室成纤维细胞和内皮细胞） 细胞）和参与心脏损伤和修复的血细胞 （中性粒细胞和单核细胞/巨噬细胞）可能影响 炎症，血流，以及电和机械 在患病的心脏中的属性。 血小板活化因子（PAF） 是一种独特的磷脂（1-O-烷基-2-乙酰基-sn-甘油-3-基）， 磷酸胆碱），其有效地激活白细胞和血小板， 并具有显著的血液动力学效应。 其生产由 内皮细胞可以作为靶向炎症的机制 细胞转移到适当的区域，或者，如果调节不当， 导致血管损伤、血栓形成和梗塞。 两 类花生酸和PAF的产生受到细胞的严格调节， 该条例有许多共同特点。 的具体目标 该项目旨在通过以下方式描述细胞机制： 这两种途径的起始步骤，磷脂酶激活， 以及如何在其他步骤中实施监管， 途径。 选择要研究的细胞是因为它们 与心血管疾病的相关性及其作为 相关生化过程的实验模型。 我们 将研究几种信号转导机制， 我们和其他人在这些过程中受到牵连， 广泛地利用我们在不同的调节改变的发现， 作为调控机制的探针。 具体的问题要检查包括蛋白激酶的作用 C、Ca流和G蛋白在调节PAF和类花生酸中的作用 生产 这些研究将使用分离的细胞和培养的细胞 被代谢标记，或用作酶的来源， 测定，然后进行分析程序，包括 色谱法、免疫测定法、光谱测定法和 电泳

The goal of this project is to understand how the production of eicosanoids (prostaglandins and leukotrienes) and platelet- activating factor are regulated in several cells relevant to cardiovascular disease. Eicosanoids are oxygenated metabolites of arachidonic acid that have diverse, potent effects on pathophysiological processes. Their production by cardiac cells (including the pericardium, ventricular fibroblasts, and endothelial cells) and by blood cells involved in cardiac injury and repair (neutrophils and monocytes/macrophages) may influence inflammation, blood flow, and electrical and mechanical properties in the diseased heart. Platelet-activating factor (PAF) is a unique phospholipid (1-0-alkyl-2-acetyl-sn-glycero-3- phosphocholine) that potently activates leukocytes and platelets, and has marked hemodynamic effects. Its production by endothelium could serve as a mechanism to target inflammatory cells to an appropriate area or, if incorrectly regulated, could result in vascular injury, thrombosis, and infarction. Both eicosanoids and PAF production are tightly regulated by cells, and the regulation has many common features. The specific aims of this project are directed at describing the cellular mechanisms by which the initial step in both pathways, phospholipase activation, is achieved and how regulation is exerted at other steps in the pathways. The cells to be studied have been chosen for their relevance to cardiovascular disease and their suitability as experimental models for the relevant biochemical processes. We will examine several mechanisms for signal transduction that have been implicated by us and others in those processes, and will extensively utilize our finding of altered regulation at different times in culture as a probe for the regulatory mechanisms. Specific issues to be examined include the roles of protein kinase C, Ca flux, and G proteins in regulating PAF and eicosanoid production. The studies will use isolated cells and cultured cells that are metabolically labeled, or used as a source for enzymatic assays, followed by analytical procedures including chromatography, immunoassay, spectrometry, and electrophoresis.