PLATELET ACTIVATION WITH OBESITY PROMOTES ATHEROTHROMBOTIC VASCULAR EVENTS

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 子项目4说明 肥胖与心血管死亡风险增加有关。肥胖相关心血管死亡的一个潜在因素可能与脂肪质量增加引起的血栓前状态和炎症状态有关，这两种状态都是动脉粥样硬化临床表现发病机制的关键组成部分。血小板在动脉血栓形成中起中心作用，在炎症状态下被激活，并直接受到特定脂肪因子的影响，因此有可能成为肥胖导致的心血管后果的重要中介。α颗粒对于正常的血小板活动是必不可少的。许多炎症因子和细胞因子储存在颗粒中。激活的但不是静止的血小板能够通过诱导单核细胞趋化蛋白(MCP-1)的分泌来改变内皮细胞的趋化特性。同样，转化生长因子-β(TGF-β)是从活化的血小板α颗粒中释放出来的，并已被证明可以促进脂肪组织释放1型纤溶酶原激活物抑制物(PAI-1)。因此，血小板分泌可能在饮食诱导肥胖的促炎和促血栓形成后果中发挥重要作用。CGMP/PKG通路在血小板分泌中起关键作用。此外，我们最近确定了Src家族亲属，特别是Lyn激酶，在血小板分泌中的作用。因此，我们将操纵这些信号通路，以确定血小板分泌在肥胖相关的促炎和促血栓状态中的作用。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Sub-project 4 description Obesity is associated with an increased risk of cardiovascular death. One potential contributing factor in obesity-associated cardiovascular deaths may be related to the pro-thrombotic and pro-inflammatory states induced by increases in adipose mass, both of which are critical components of the pathogenesis of the clinic manifestations of atherosclerosis. Platelets play a central role in arterial thrombosis, are activated in inflammatory states, and are directly influenced by specific adipokines, and therefore have the potential to serve as an essential mediator of the cardiovascular consequences of obesity. alpha-Granules are essential to normal platelet activity. Many inflammatory factors and cytokines are stored in ¿-Granules. Activated, but not resting platelets are able to alter the chemotactic properties of endothelial cells by inducing the secretion of monocyte chemoattractant protein (MCP-1). Similarly, transforming growth factor-beta (TGF-beta) is released from activated platelet alpha-granules and has been shown to augment the release of type-1 plasminogen activator inhibitor (PAI-1) from adipose tissue. Therefore, platelet secretion may play an important role in the pro-inflammatory and pro-thrombotic consequences of diet-induced obesity. The cGMP/PKG pathway plays a critical role in platelet secretion. In addition, we have recently identified a role for Src family kinses, especially the Lyn kinase, in platelet secretion. Therefore, we will manipulate these signaling pathways to identify a role of platelet secretion in obesity-associated pro-inflammatory and pro-thrombotic states.