PHOSHOINOSITTIDE METABOLISM AND PLATELET SECRETION

磷酸肌醇代谢和血小板分泌

• 批准号: 3354909
• 负责人: SUSAN E RITTENHOUSE
• 金额: $ 12.86万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-09-01 至 1991-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3354909
• 关键词: arachidonate; bacterial toxins; calcium; cyclic GMP; cytoskeleton; diacylglycerols; eicosanoid metabolism; enzyme induction /repression; epinephrine; gas chromatography; gel electrophoresis; high performance liquid chromatography; human tissue; ion exchange chromatography; lipid metabolism; phorbols; phosphatidylinositols; phospholipase C; platelets; prostaglandins; protein kinase C; secretion; thin layer chromatography; thrombin; thromboxanes

The human platelet is a major participant, normally and pathophysiologically, in coagulation and thrombosis, and can affect the contractile response of vascular tissue. Platelets also contribute to the formation of arterial plaques. Activation of platelet is dependent upon Ca-2-+ mobilization and secretion of material in platelet storage granules. Stimulated platelets display very rapid and marked alterations in phosphoinositide metabolism prior to Ca-2-+ mobilization and secretion. Increasing evidence indicate that breakdown of phosphoinositides (PtdIns, PtdIns4,5P-2) by phospholipase C (PLC) causes the mobilization of Ca-2-+ via myoinositol trisphosphate (IP-3), and activation of kinase by diacylglycerol (DG), which promote platelet morphological changes. Conversic of released arachidonic acid to prostaglandin metabolites can also participate in such activation of PLC. Utilizing techniques of capillary gas chromatography, electrophoresis, thin layer, ion exchange, and high pressure liquid chromatographies, as well as high voltage membrane permeabilization, all routinely performed in our laboratory, we will address the following questions: 1) How is PLC regulated? 2) Is the action of PLC on phosphatidylinositol (PtdIns) dependent upon hydrolysis of PtdIns4,5P-2? 3) What is the function of IP-3 in platelets? 4) Does epinephrine potentiate prostaglandin-related phosphoinositide metabolism? 5) Why is thrombin a more effective agonist for arachidonic acid release than is the prostaglandin H-2/thromboxane A-2 analogue U46619? Clarification of the factors (and their mechanisms of action) that affect phosphoinositide turnover and elucidation of the synergistic activation of platelets by epinephrine should enhance our understanding of events controlling platelet function in normal and pathological states.

人类血小板是主要参与者，通常情况下， 病理生理学上，在凝血和血栓形成中，并且可以影响 血管组织的收缩反应。 血小板还有助于 动脉斑块的形成。 血小板的活化取决于 血小板储存中 Ca-2-+ 动员和物质分泌 颗粒。 受刺激的血小板显示出非常快速且显着的变化 在 Ca-2-+ 动员和分泌之前的磷酸肌醇代谢中。 越来越多的证据表明磷酸肌醇（PtdIns、 PtdIns4,5P-2) 通过磷脂酶 C (PLC) 引起 Ca-2-+ 的动员 通过三磷酸肌醇 (IP-3)，并通过以下方式激活激酶 二酰基甘油（DG），促进血小板形态变化。 释放的花生四烯酸可转化为前列腺素代谢物 也参与PLC的此类激活。 利用毛细管气相色谱、电泳、薄层技术 层析、离子交换和高压液相色谱，以及 高压膜透化，全部在我们的实验室中常规进行 实验室，我们将解决以下问题： 1）PLC是如何监管的？ 2）PLC对磷脂酰肌醇有作用吗 (PtdIns) 取决于 PtdIns4,5P-2 的水解？ 3）什么是 IP-3在血小板中的功能？ 4）肾上腺素有增强作用吗？ 前列腺素相关的磷酸肌醇代谢？ 5) 为什么凝血酶是 比花生四烯酸释放更有效的激动剂 前列腺素 H-2/血栓素 A-2 类似物 U46619？ 澄清影响因素（及其作用机制） 磷酸肌醇周转和协同激活的阐明 肾上腺素检测血小板应该增强我们对事件的理解 在正常和病理状态下控制血小板功能。