Exocytosis and Vascular Inflammation

胞吐作用和血管炎症

• 批准号: 7115398
• 负责人: CHARLES J LOWENSTEIN
• 金额: $ 31.93万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-24 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7115398
• 关键词: adenosinetriphosphatase; confocal scanning microscopy; enzyme activity; enzyme linked immunosorbent assay; exocytosis; inflammation; laboratory mouse; maleimides; nitric oxide; selectins; superoxide dismutase; thrombosis; vascular endothelium; von Willebrand factor

DESCRIPTION (provided by applicant): Endothelial cells play a critical role in the initiation of vascular inflammation and thrombosis. Stimulated by vascular injury or inflammatory agonists, endothelial cells express mediators that regulate leukocyte trafficking and platelet activation. The kinetics of endothelial activation include an early phase mediated by the rapid release of previously synthesized factors, and a later phase mediated by the synthesis of new proteins. The early inflammatory response of endothelial cells includes the exocytosis of Weibel-Palade bodies, endothelial granules that contain yon Willebrand Factor (vWF) and P-selectin. Exocytosis of Weibel-Palade bodies releases vWF which regulates platelet adhesion and aggregation, and translocates P-selectin to the endothelial surface where it regulates leukocyte rolling. Thus endothelial exocytosis plays an important role in mediating vascular inflammation and thrombosis. The regulation of endothelial exocytosis is partially understood. Exocytosis is a form of vesicle trafficking in which the granule fuses with the cellular plasma membrane, releasing its contents into the extracellular space and translocating transmembrane proteins to the surface of the cell. Several families of proteins regulate exocytosis, including N-ethylmaleimide sensitive factor (NSF), soluble NSF attachment protein receptors (SNAREs), rab GTPases, and Munc. We recently showed that NSF plays a critical role in the regulation of exocytosis of Weibel-Palade bodies. We also discovered that nitric oxide (NO) inhibits exocytosis by targeting NSF. Our observations explain in part how NO inhibits vascular inflammation and thrombosis. The over-all goal of our studies is to explore the molecular mechanisms by which endothelial exocytosis regulates vascular inflammation. This application focuses on NSF regulation of endothelial cell exocytosis. We plan to continue our studies of how radicals regulates NSF. Next we plan to study how specific enzymes reduce oxidized NSF. Finally, we plan to develop a novel class of drugs that decrease vascular inflammation by targeting endothelial cell exocytosis.

描述（由申请人提供）： 内皮细胞在血管炎症和血栓形成的引发中起着关键作用。在血管损伤或炎症激动剂的刺激下，内皮细胞表达调节白细胞运输和血小板活化的介质。内皮激活的动力学包括由先前合成的因子的快速释放介导的早期阶段和由新蛋白质的合成介导的后期阶段。内皮细胞的早期炎症反应包括 Weibel-Palade 小体、含有维勒布兰德因子 (vWF) 和 P-选择素的内皮颗粒的胞吐作用。 Weibel-Palade 小体的胞吐作用释放 vWF，调节血小板粘附和聚集，并将 P-选择素转移到内皮表面，调节白细胞滚动。因此，内皮胞吐作用在介导血管炎症和血栓形成中起着重要作用。 内皮胞吐作用的调节已部分了解。胞吐作用是囊泡运输的一种形式，其中颗粒与细胞质膜融合，将其内容物释放到细胞外空间并将跨膜蛋白易位到细胞表面。多个蛋白质家族调节胞吐作用，包括 N-乙基马来酰亚胺敏感因子 (NSF)、可溶性 NSF 附着蛋白受体 (SNARE)、rab GTPases 和 Munc。我们最近表明 NSF 在 Weibel-Palade 小体胞吐作用的调节中发挥着关键作用。我们还发现一氧化氮 (NO) 通过靶向 NSF 来抑制胞吐作用。 我们的观察部分解释了 NO 如何抑制血管炎症和血栓形成。 我们研究的总体目标是探索内皮胞吐作用调节血管炎症的分子机制。本申请重点关注 NSF 对内皮细胞胞吐作用的调节。 我们计划继续研究激进分子如何监管 NSF。接下来我们计划研究特定的酶如何减少氧化的 NSF。最后，我们计划开发一类新型药物，通过针对内皮细胞胞吐作用来减少血管炎症。