Mechanisms of Effect of Aspirin on Cerebral Aneurysms in Mice

描述（由申请人提供）：炎症似乎在脑动脉瘤的形成、其进展为破裂倾向型并最终破裂中起关键作用。支持这一假设的证据包括来自人类神经外科患者和实验动物模型的最新数据，这些数据表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，检查脑动脉瘤破裂患者服用阿司匹林是否降低了动脉瘤破裂的风险。本研究使用未破裂颅内动脉瘤国际研究数据库进行。每周使用三次阿司匹林的患者动脉瘤破裂的风险显著降低。我目前的科学目标，也是这个提议的主题，是研究炎症影响脑动脉瘤形成和破裂的分子机制。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中，我将确定考克斯-1和考克斯-2对阿司匹林预防动脉瘤破裂的保护作用的贡献。在具体目标2中，我将确定细胞 与考克斯-2通路的激活相关，导致对动脉瘤破裂的保护作用。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。了解动脉瘤形成和破裂的炎症相关分子机制将提供对于为患有这种危险脑血管疾病的患者开发有效的新医学疗法至关重要的信息。

DESCRIPTION (provided by applicant): 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 ruptured 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 have 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 wit this dangerous cerebrovascular disease.