Mechanisms of Effect of Aspirin on Cerebral Aneurysms in Mice

项目总结/摘要 炎症似乎在脑动脉瘤的形成及其破裂过程中起着关键作用- 倾向型，并最终破裂。支持这一假设的证据包括来自人类的最新数据 神经外科患者和实验动物模型证明动脉瘤壁组织富含 巨噬细胞和炎症分子。为了研究这一假设的潜在治疗意义， 我进行了一项回顾性研究，检查未破裂的脑动脉瘤患者是否服用了 阿司匹林降低了动脉瘤破裂的风险。这项研究是使用国际研究进行的， 未破裂颅内动脉瘤数据库。每周三次至每天服用阿司匹林的患者， 显著降低动脉瘤破裂的风险。我目前的科学目标，以及这个提议的主题， 研究炎症影响脑动脉瘤形成的分子机制， 破裂我正在使用完善的Hashimoto小鼠动脉瘤模型来追求两个特定的目标。在 具体目标1，我将确定考克斯-1和考克斯-2对阿司匹林保护作用的贡献， 动脉瘤破裂在具体目标2中，我将确定与考克斯-2激活相关的细胞类型 导致对动脉瘤破裂的保护作用的通路。这些研究将涉及使用 互补的遗传学、药理学和骨髓移植实验方法。 动脉瘤形成和破裂的炎症相关分子机制的知识将提供 这些信息对于为患有这种疾病的患者开发有效的新医学疗法至关重要 危险的脑血管疾病

PROJECT SUMMARY/ABSTRACT Inflammation appears to play a critical role in the formation of cerebral aneurysms, their progression to rupture- prone type, and ultimately to rupture. Evidence supporting this hypothesis includes recent data from human neurosurgery patients and experimental animal models demonstrating that aneurysm wall tissue is rich with macrophages and inflammatory molecules. To investigate potential therapeutic implications of this hypothesis, I carried out a retrospective study examining whether patients with unruptured cerebral aneurysms who took aspirin had a reduced risk of aneurysm rupture. This study was performed using the International Study of Unruptured Intracranial Aneurysms data base. Patients who used aspirin three times weekly to daily had a significantly decreased risk of aneurysm rupture. My current scientific goals, and the subject of this proposal, are to study the molecular mechanisms by which inflammation influences cerebral aneurysm formation and rupture. I am using the well-established Hashimoto mouse aneurysm model to pursue two specific aims. In Specific Aim 1, I will determine the contributions of COX-1 and COX-2 to the protective effect of aspirin against aneurysm rupture. In Specific Aim 2, I will determine the cell type associated with activation of the COX-2 pathway resulting in a protective effect against aneurysm rupture. These studies will involve the use of complementary genetic, pharmacological and bone marrow transplantation experimental approaches. Knowledge of the inflammation related molecular mechanisms of aneurysm formation and rupture will provide information that is critical to the development of effective new medical therapies for patients with this dangerous cerebrovascular disease.