Mechanisms for intracranial aneurysm rupture

项目摘要 中性粒细胞和血小板在颅内动脉瘤病理生理学中的潜在作用由来已久。 临床观察提示。然而，中性粒细胞和血小板工作的确切机制 促进颅内动脉瘤破裂的机制尚不清楚。激活的中性粒细胞可以释放 去凝集的DNA用中性粒细胞弹性蛋白酶和髓过氧化物酶等中性粒细胞酶装饰， 导致中性粒细胞胞外陷阱(NETs)的形成和中性粒细胞的死亡(NETsis)。 网络最初被描述为一种可以捕获和溶解病原体的结构。然而，最近的研究 提示Net在包括动脉粥样硬化在内的涉及血管炎症的无菌疾病中的作用 脉管炎和静脉血栓形成。Net和血小板之间的相互作用可能导致恶性循环 网状形成和血小板活化，导致过度的血管壁损伤和动脉瘤 破裂。我们的初步研究表明，Net在人类颅内动脉瘤和实验性脑动脉瘤中都存在。 小鼠动脉瘤。此外，缺乏精氨酸脱亚胺酶-4(PAD4)的小鼠，精氨酸脱氨酶-4是 净形成，有较低的破损率。 我们推测，中性粒细胞胞外陷阱Net可以促进颅内病变的发生。 动脉瘤破裂通过中性粒细胞和血小板激活的恶性循环。在目标1中，我们将测试中性粒细胞 与对照小鼠相比，PAD4缺陷小鼠的破裂率较低，网状结构减少。在……里面 目的2，我们将测试PAD4抑制剂(氯-嘧啶)对Net形成的药理预防作用 和GSK484)或通过脱氧核糖核酸酶对Net的拆分可以减少动脉瘤破裂。在《目标3》中，我们将 检测血小板和中性粒细胞-血小板的相互作用是否会导致动脉瘤破裂。我们将测试 血小板减少的小鼠是否减少了净形成和较低的破裂率。我们亦会研究 P-选择素或CD11b/CD18介导的中性粒细胞-血小板相互作用在高血压发病中的作用 动脉瘤破裂。 拟议的研究将提供新的见解，以了解网络的作用及其与血小板的相互作用。 动脉瘤破裂的发展。这一结果将成为未来研究开发新疗法的基础 靶网和血小板-中性粒细胞相互作用预防动脉瘤破裂。

Project Summary Potential roles of neutrophils and platelets in the pathophysiology of intracranial aneurysms have been long suggested by clinical observations. However, the exact mechanism by which neutrophils and platelets work to promote the rupture of intracranial aneurysms is not well understood. Activated neutrophils can release decondensed DNA decorated with neutrophil enzymes such as neutrophil elastase and myeloperoxidase, resulting in the formation of Neutrophil Extracellular Traps (NETs) and the death of neutrophils (NETosis). NETs were originally described as a structure that can trap and dissolve pathogens. However, recent studies suggest roles of NETs in sterile diseases that involve vascular inflammation including atherosclerosis, vasculitis, and venous thrombosis. Interactions between NETs and platelets may result in a vicious cycle of NET formation and platelet activation that leads to the excessive vascular wall damages and aneurysmal rupture. Our preliminary studies show that NETs exist in both human intracranial aneurysms and experimental mouse aneurysms. In addition, mice lacking protein arginine deiminases-4 (PAD4), an enzyme required for the NET formation, had a reduced rupture rate. We hypothesize that NETs, neutrophil extracellular traps, can promote the development of intracranial aneurysm rupture through the vicious cycle of neutrophil and platelet activation. In Aim 1, we will test neutrophil PAD4-deficient mice have a lower rupture rate and reduce NET formations compared to the control mice. In Aim 2, we will test whether the pharmacological prevention of NET formation by PAD4 inhibitors (Cl-amidine and GSK484) or the resolution of NETs by deoxyribonuclease reduces aneurysmal rupture. In Aim 3, we will test whether platelets and neutrophil-platelet interactions contribute to aneurysmal rupture. We will test whether thrombocytopenic mice have reduced NET formations and lower rupture rates. We will also study the contribution of P-selectin or CD11b/CD18-mediated neutrophil-platelet interactions to the development of aneurysmal rupture. The proposed studies will provide new insights into the roles of NETs and their interactions with platelets in the development of aneurysmal rupture. The results will be a basis for future studies to develop new therapies that target NETs and platelet-neutrophil interactions for the prevention of aneurysmal rupture.