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。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。为了改变刚刚为患有未破裂的颅内动脉瘤的人所描述的严峻前景，提出了一项成功的研究计划，重点是研究在兔身上制造的真实的人体动脉瘤模型。这个模型已经经过了广泛的验证，并被用来更好地理解动脉瘤中与破裂相关的血流改变的作用。在目前的提案中，我们将实现进一步研究动脉瘤的四个重要目标：1)将包括基因组和蛋白质组在内的先进技术应用到模型中；2)将被许多研究人员视为破裂预测因子的动脉瘤形状与动脉瘤内血管壁的血流变化和功能紊乱相关联；3)应用该模型来提高对许多情况下微创弹簧圈未能闭塞动脉瘤的原因的理解；以及4)将弹簧圈治疗后动脉瘤附近的血流进行关联，以了解弹簧圈失效的机制。这些目标中的每一个都将通过创建动脉瘤模型来实现，然后与一个由放射科医生、机械工程师、分子生物学家和计算机科学家组成的多学科、多机构的团队合作，将先进的成像技术、分子生物学、基因组学和计算流体力学研究应用到模型中。这项计划将通过预防因颅内动脉瘤自发性破裂而导致的灾难性事件来增进健康。

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. 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 build upon a successful research program focused on the study of a realistic model of human aneurysms that is created in rabbits. This model has already undergone extensive validation and been used to better understand the role of altered flow in aneurysms as related to rupture. In the current proposal we will achieve four important aims to further aneurysm research: 1) applying advanced techniques, including genomics and proteomics, to the model; 2) correlating aneurysm shape, considered a predictor for rupture by many investigators, with altered flow and disturbed function of the vessel wall within aneurysms; 3) applying the model to improve the understanding of why minimally invasive coils fail to occlude aneurysms in many cases; and 4) correlating flow near aneurysms after coil treatment to understand mechanisms of coil failure. Each of these aims will be achieved by creating model aneurysms and then, working with a multidisciplinary, multi-institutional team comprising Radiologists, Mechanical Engineers, Molecular Biologists, and Computer Scientists, applying advanced imaging techniques, molecular biology, genomics, and computational fluid dynamics studies to the model. This program will enhance health by preventing the catastrophic events resulting from spontaneous rupture of intracranial aneurysms.