Improved Animal Modeling of Saccular Aneurysms

描述(申请人提供)：在美国，未破裂的颅内动脉瘤出现在大约4%-5%的普通人群中。一旦确诊，可能很难有信心地推荐适当的治疗方法。可供选择的方法有：(1)开腹手术夹闭动脉瘤；(2)较小侵入性的影像引导下血管导航，放置封堵动脉瘤腔的装置；或(3)观察。手术是治愈的，但有17%的严重副作用风险。血管内放置闭塞装置的风险较低(5-7%)，但永久性动脉瘤闭合率不佳；许多情况下会发生随后的再生长。观察有破裂的风险，这在大多数情况下是致命的，对大多数幸存者的神经损害。 为了改变上述对患有未破裂颅内动脉瘤的人的严峻前景，建议开展工作以实现进一步动脉瘤研究的三个重要目标：1)验证新的人类动脉瘤动物模型；2)探讨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，后者可能是破裂的初始触发因素；3)验证一项新的技术，用于处理动物和人类组织中含有血管内线圈的组织，并展示兔和人类之间的组织反应之间的同源性。这些目标目前可以有效地实现，因为该计划在神经血管研究的基础设施方面引入了两个主要进展：模拟人类颅内动脉瘤的重要特征的动物模型，以及组织处理的新方法，该方法将首次允许对植入闭塞装置的生物反应进行常规评估。具体的研究设计进展如下：验证动物模型的长期行为；研究动脉瘤血流动力学和内皮细胞功能；使用动物模型确认新的组织处理方法的实用性；以及使用该方法比较动物和人类之间放置治疗性闭塞装置的细胞反应。 这项研究计划将(1)提供对动脉瘤破裂的重要细胞机制的洞察，(2)推进必要的基础工作，以提高微创治疗的有效性，以及(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，通过预防由颅内动脉瘤自发性破裂导致的灾难性事件来增强健康。

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.