Mechanisms for intracranial aneurysm rupture

颅内动脉瘤破裂的机制

基本信息

批准号：
10531881
负责人：
TOMOKI HASHIMOTO
金额：
$ 38.73万
依托单位：
ST. JOSEPH'S HOSPITAL AND MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10531881
关键词：
Amidines Aneurysm Antibodies Aspirin Atherosclerosis Blood Platelets Blood Vessels Cessation of life Clinical Clinical Research Clip DNA Deoxyribonucleases Deposition Development Disease Endothelium Enzymes Fibrin Functional disorder Future Human ITGAM gene ITGB2 gene Inflammation Intracranial Aneurysm Knockout Mice Laboratories Leukocyte Elastase Link Macrophage Mediating Morbidity - disease rate Mus Neutrophil Activation Neutrophil Infiltration P-Selectin Patients Peroxidases Plasma Platelet Activation Platelet aggregation Prevention Protein Inhibition Protein-arginine deiminase Resolution Risk Role Rupture Ruptured Aneurysm Site Sterility Structure Subarachnoid Hemorrhage Testing Therapeutic Thrombosis Thrombus Tissues Vasculitis Venous Thrombosis Work adverse outcome comparison control extracellular inhibitor insight migration mortality mouse model neutrophil new therapeutic target pathogen pharmacologic prevent vascular inflammation

项目摘要

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.

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已很长由临床观察提出。但是，中性粒细胞和血小板的确切机制可尚不清楚促进颅内动脉瘤的破裂。激活的中性粒细胞可以释放用中性粒细胞酶（如中性粒细胞弹性酶和髓过氧化物酶）装饰的dnon限性DNA，导致嗜中性粒细胞外陷阱（网）和中性粒细胞死亡（Netosis）形成。网最初被描述为可以捕获并溶解病原体的结构。但是，最近的研究建议在涉及血管炎症（包括动脉粥样硬化）的无菌疾病中的网中作用血管炎和静脉血栓形成。网和血小板之间的相互作用可能导致恶性循环净形成和血小板激活导致过度血管壁伤害和动脉瘤破裂。我们的初步研究表明，网络存在于人类颅内动脉瘤和实验性中鼠标动脉瘤。此外，缺乏蛋白精氨酸脱氨酶-4（PAD4）的小鼠，这是一种酶净形成，破裂率降低。我们假设网络，中性粒细胞外陷阱可以促进颅内发展动脉瘤通过中性粒细胞和血小板激活的恶性循环破裂。在AIM 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，净地层降低。在 AIM 2，我们将测试PAD4抑制剂对净形成的药理预防（CL-酰胺定和GSK484）或脱氧核糖核酸酶解决的净分辨率可减少动脉瘤破裂。在AIM 3中，我们将测试血小板和中性粒细胞 - 血小板相互作用是否有助于动脉瘤破裂。我们将测试血小板减少小鼠是否降低了净形成和降低破裂率。我们还将研究 p-选择素或CD11b/CD18介导的中性粒细胞 - 血压相互作用对发展的贡献动脉瘤破裂。拟议的研究将为网中的作用及其与血小板的相互作用提供新的见解动脉瘤破裂的发展。结果将是未来研究开发新疗法的基础靶网和血小板中性嗜性相互作用可预防动脉瘤破裂。