Improved Animal Modeling of Saccular Aneurysms

描述（由申请人提供）：在美国，未破裂的颅内动脉瘤约占一般人群的4-5%。一旦确诊，可能很难有信心地推荐适当的治疗。选择有（1）开放手术夹闭动脉瘤;（2）微创、影像引导导航通过血管置入器械闭塞动脉瘤腔;或（3）观察。手术是治愈性的，但有17%的严重副作用的风险。闭塞器械的血管内置入风险较低（5-7%），但永久性动脉瘤闭合率不理想;许多病例随后发生再生长。观察有破裂的风险，这在大多数情况下是致命的，并对大多数幸存者造成神经损伤。 为了改变上述未破裂颅内动脉瘤患者的严峻前景，提出了进一步研究动脉瘤的三个重要目标：1）验证新的人类动脉瘤动物模型; 2）探索动脉瘤血流动力学和内皮细胞功能障碍之间的复杂相互作用，这可能是动脉瘤破裂的初始触发因素;和3）验证用于处理带有血管内弹簧圈的动物和人体组织的新技术，并证明兔和人体组织反应之间的同源性。这些目标可以有效地解决在这个时候，因为引入了两个重大进展的基础设施的神经血管研究的这个程序：动物模型模仿人类颅内动脉瘤的重要特征，和一种新的组织处理方法，应该允许，第一次，常规评价的生物反应植入闭塞装置。具体的研究设计进展如下：动物模型的长期行为的验证;动脉瘤血流动力学和内皮细胞功能的研究;使用动物模型来确认新的组织处理方法的效用;以及，使用该方法来比较动物和人类之间对治疗性闭塞器械放置的细胞反应。 该研究计划将（1）深入了解动脉瘤破裂的重要细胞机制，（2）为提高微创治疗的有效性提供必要的基础，（3）产生一个强大的，具有良好特征的动物模型，用于进一步的研究开发，以通过预防颅内动脉瘤自发破裂导致的灾难性事件来改善健康。

DESCRIPTION (provided by applicant): In the United States, unruptured intracranial aneurysms are present in approximately 4-5% of the general population. Once diagnosed, appropriate therapy may be difficult to recommend with confidence. The choices are (1) open surgery to clip the aneurysm; (2) less invasive, imaging-guided navigation through vessels for placement of a device to occlude the aneurysm cavity; or, (3) observation. Surgery is curative, but carries a 17% risk of serious side effects. Endovascular placement of occlusion devices involves lower risk (5-7%), but suboptimal rates of permanent aneurysm closure; subsequent regrowth occurs in many cases. Observation carries a risk of rupture, which is fatal in the majority of cases and neurologically damaging to the majority of survivors. With the objective of altering the grim outlook just described for persons harboring unruptured intracranial aneurysms, work is proposed to achieve three important goals to further aneurysm research: 1) to validate of a new animal model of human aneurysms; 2) to probe the complex interaction between aneurysm hemodynamics and endothelial cell dysfunction, which may represent the initial trigger for rupture; and 3 ) to validate a new technique for processing both animal and human tissue bearing endovascular coils, and to demonstrate homology between the tissue reaction in rabbits and humans. These goals can be effectively addressed at this time because of the introduction with this program of two major advances in the infrastructure for neurovascular research: an animal model mimicking important characteristics of human intracranial aneurysms, and a new method for tissue processing that should allow, for the first time, routine evaluation of the biological response to implantation of occlusion devices. The specific research design progresses as follows: validation of the long-term behavior of the animal model; study of aneurysm hemodynamics and endothelial cell function; use of the animal model to confirm the utility of the new tissue-processing method; and, use of the method to compare cellular responses to the placement of therapeutic occlusion devices between animals and humans. This research program will (1) offer insight into the cellular mechanisms important in rupture of aneurysms, (2) advance groundwork necessary for improving the efficacy of minimally invasive therapy, and, (3) yield a robust, well-characterized animal model for use in further research developments to enhance health by preventing the catastrophic events resulting from spontaneous rupture of intracranial aneurysms.