BIOCHEMISTRY OF MAST CELL MEDIATOR RELEASE

肥大细胞释放的预形成和新形成的介质在调节肥大细胞的增殖中起着重要作用。 在保护性或病理性速发型超敏反应中的中心作用 反应. 肥大细胞介质的释放似乎也有助于一些 补体介导的反应，以表达或调节 淋巴细胞介导的反应，对某些形式的非特异性炎症， 和一些生理反应。 这一长期目标 建议是解决肥大细胞膜融合的生化基础 - 预先形成的介质释放的机制;以及 花生四烯酸-几种新形成的介质的前体。 最近 这个实验室和其他实验室的实验提供了生物学 在大鼠肥大细胞中的先例和直接证据表明， sn-1，2-二酰基甘油（DAG）和磷脂酸（PA）的代谢可 在肥大细胞介质释放中起关键作用。 的具体目标 这一建议是：1.）研究DAG的起源和命运， 刺激大鼠肥大细胞，特别强调磷脂酶C， 磷脂酸磷酸水解酶、DAG激酶和DAG-脂肪酶; 2.）测量 其他促融合脂质在刺激大鼠中的水平、来源和转归 肥大细胞，重点是DAG、sn-1或2-单酰基甘油和 溶血磷脂; 3.）研究新成立的PA的起源和命运 在刺激的肥大细胞中; 4.）来确定 花生四烯酸（AA）可用于合成新形成的介质 在刺激的肥大细胞中; 5.）探测细胞内系统， 控制这些反应;和6.）以确定老鼠桅杆 细胞表达被DAG（“蛋白激酶”）激活的蛋白激酶活性 激酶C”），如果存在，则详细表征活性。 导致膜形成的反应的鉴定和表征 肥大细胞中的融合和AA可用性是 在分子水平上理解IgE介导的反应。 改进 了解介质释放的机制可能允许 制定有目的的监管新方法， 最终可能被应用于改善人类过敏或 其他炎症性疾病。

Preformed and newly formed mediators released from mast cells play a central role in protective or pathologic immediate hypersensitivity reactions. Mast cell mediator release also appears to contribute to some complement-mediated reactions, to the expression or regulation of lymphocyte-mediated reactions, to some forms of nonspecific inflammation, and to some physiologic responses. The long term objectives of this proposal are to resolve the biochemical basis of mast cell membrane fusion - the mechanism of preformed mediators release; and the release of arachidonic acid - the precursor of several newly formed mediators. Recent experiments in this and other laboratories have provided biologic precedents and direct evidence in rat mast cells that alterations in the metabolism of sn-1,2-diacylglycerol (DAG) and of phosphatidic acid (PA) may play pivotal roles in mast cell mediator release. The specific aims of this proposal are: 1.) to examine the origins and fates of DAG in stimulated rat mast cells with particular emphasis on phospholipase C, phosphatidate phosphohydrolase, DAG kinase and DAG-lipase; 2.) to measure the levels, origins and fates of other fusogenic lipids in stimulated rat mast cells with emphasis on DAG, sn-1 or 2-monoacylglycerol and lysophospholipids; 3.) to examine the origins and fate of newly formed P A in stimulated mast cells; 4.) to determine the reactions that make arachidonic acid (AA) available for the synthesis of newly formed mediators in stimulated mast cells; 5.) to probe the intracellular systems that regulate these reactions; and 6.) to determine whether or not rat mast cells express protein kinase activity that is activated by DAG ("protein kinase C") and if present to characterize the activity in detail. Identification and characterization of the reactions that lead to membrane fusion and AA availability in mast cells are fundamental to an understanding of Ige-mediated reactions at the molecular level. Improved knowledge of the mechanisms of mediator release might permit the development of new approaches to purposeful regulation that in turn eventually might be applied to improve the management of human allergic or other inflammatory disorders.