Mechanisms of Effect of Aspirin on Cerebral Aneurysms in Mice

阿司匹林对小鼠脑动脉瘤的作用机制

• 批准号: 8738727
• 负责人: David M. Hasan
• 金额: $ 16.79万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-30 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8738727
• 关键词: Aneurysm; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Aspirin; Attenuated; Blood Platelets; Bone Marrow Cells; Bone Marrow Transplantation; California; Cells; Cerebral Aneurysm; Cerebrovascular Disorders; Chronic; Clinical Research; Databases; Development; Devices; Dinoprostone; Drug effect disorder; Enrollment; Experimental Animal Model; Functional disorder; Genetic; Goals; Heart; Hematopoietic; Histologic; Human; Implant; Incidence; Inflammation; Inflammatory; International; Intervention; Intracranial Aneurysm; Investigation; Iowa; Knock-out; Knockout Mice; Knowledge; Laboratories; Learning; Mediating; Medical; Modeling; Molecular; Molecular Target; Mus; Neurosurgeon; PTGS2 gene; Pathway interactions; Patients; Pharmaceutical Preparations; Play; Process; Research; Retrospective Studies; Risk; Role; Rupture; Ruptured Aneurysm; San Francisco; Scientist; Stroke; Testing; Therapeutic; Time; Tissues; Training; Transplantation; Universities; Wild Type Mouse; Wit; Work; career development; cell type; cyclooxygenase 1; human WFDC2 protein; human data; inhibitor/antagonist; macrophage; mouse PGE synthase 1; neurosurgery; prevent; protective effect; public health relevance; research study; treatment strategy; Aneurysm; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Aspirin; Attenuated; Blood Platelets; Bone Marrow Cells; Bone Marrow Transplantation; California; Cells; Cerebral Aneurysm; Cerebrovascular Disorders; Chronic; Clinical Research; Databases; Development; Devices; Dinoprostone; Drug effect disorder; Enrollment; Experimental Animal Model; Functional disorder; Genetic; Goals; Heart; Hematopoietic; Histologic; Human; Implant; Incidence; Inflammation; Inflammatory; International; Intervention; Intracranial Aneurysm; Investigation; Iowa; Knock-out; Knockout Mice; Knowledge; Laboratories; Learning; Mediating; Medical; Modeling; Molecular; Molecular Target; Mus; Neurosurgeon; PTGS2 gene; Pathway interactions; Patients; Pharmaceutical Preparations; Play; Process; Research; Retrospective Studies; Risk; Role; Rupture; Ruptured Aneurysm; San Francisco; Scientist; Stroke; Testing; Therapeutic; Time; Tissues; Training; Transplantation; Universities; Wild Type Mouse; Wit; Work; career development; cell type; cyclooxygenase 1; human WFDC2 protein; human data; inhibitor/antagonist; macrophage; mouse PGE synthase 1; neurosurgery; prevent; protective effect; public health relevance; research study; treatment strategy

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.

描述（由申请人提供）：炎症似乎在脑动脉瘤的形成中起着关键作用，其发展为破裂类型，最终是破裂的。支持该假设的证据包括来自人类神经外科患者的最新数据和实验动物模型，表明动脉瘤壁组织富含巨噬细胞和炎症分子。为了研究该假设的潜在治疗意义，我进行了一项回顾性研究，研究了服用阿司匹林的脑动脉瘤破裂的患者是否降低了动脉瘤破裂的风险。这项研究是使用国际颅内动脉瘤数据库的国际研究进行的。每周三次使用阿司匹林的患者每天的动脉瘤破裂风险大大降低。我目前的科学目标以及该提案的主题是研究炎症影响脑动脉瘤形成和破裂的分子机制。我正在使用良好的Hashimoto小鼠动脉瘤模型来追求两个具体目标。在特定的目标1中，我将确定COX-1和COX-2对阿司匹林对动脉瘤破裂的保护作用的贡献。在特定的目标2中，我将确定单元格 类型与COX-2途径的激活相关，从而对动脉瘤破裂产生保护作用。这些研究将涉及互补的遗传，药理和骨髓移植实验方法的使用。了解与炎症相关的动脉瘤形成和破裂的分子机制的知识将提供有关这种危险脑血管疾病的有效新医疗疗法至关重要的信息。