AAA Disease: Mechanism, Stratification and Treatment

腹主动脉瘤（AAA）是美国老年人中一种常见的、病态的、经常致命的疾病。AAA疾病的主要临床挑战包括：1)缺乏有效的非手术治疗来预防早期疾病的进展；2)有效的生物标志物或有效的成像指标来监测疾病活动并指导小动脉瘤的抑制性药物治疗。基于大量的先前证据表明，可变的主动脉流量和壁剪切应力条件可调节血管炎症，本SCCOR提出：1)确定和验证AAA疾病分层的新生物标志物和成像策略，2)测试运动疗法抑制小AAA的能力，以及3)研究实验AAA进化过程中存在的关键分子和细胞事件，以确定和完善新的治疗策略。项目一（凝血酶裂解骨桥蛋白在AAA中的作用）将研究凝血酶裂解骨桥蛋白及其在AAA中的调节作用，并确定特定裂解形式的骨桥蛋白的测量是否将作为预测疾病进展的有用生物标志物。项目II（识别AAA的特征蛋白谱）将开发一种定制的基于抗体的蛋白质阵列，以测试是否可以识别与不同大小AAA相关的不同特征蛋白谱，以及这些谱的变化是否可以预测疾病进展和对干预的反应。项目III （AAA进展中的血流动力学）将使用基于mri的成像技术表征AAA患者在静息和运动条件下的肾下主动脉血流动力学。我们将研究动脉瘤的形状、大小或血管壁结构如何影响AAA的血流动力学参数，并测试这些血流和血管壁特征的变化是否预测疾病进展和对干预的反应。项目四（小型AAA运动治疗评估）是SCCOR应用的重点项目。一项前瞻性随机试验将进行，以测试一个监督和持续的运动计划是否会降低患者的小AAA扩张率。该临床试验将锚定并连接SCCOR的所有其他项目。拟议的SCCOR将使许多具有互补专业知识的有成就的研究人员能够开发一种协调和综合的方法来分析、分层和治疗AAA疾病，并实现SCCOR将知识转化为临床实践的目标。

Abdominal aortic aneurysm (AAA) is a common, morbid, and frequently lethal disease of older Americans. Major clinical challenges in AAA disease include the absence of: 1) effective non-surgical therapies to prevent progression of early stage disease, and 2) validated biomarkers or efficient imaging indices to monitor disease activity and guide suppressive medical therapies in small aneurysms. Based on extensive prior evidence demonstrating that variable aortic flow and wall shear stress conditions modulate vascular inflammation, this SCCOR proposes to: 1) Identify and validate novel biomarkers and imaging strategies for AAA disease stratification, 2) Test the ability of exercise therapy to suppress small AAAs, and 3) Investigate key molecular and cellular events present during experimental AAA evolution to identify and refine novel therapeutic strategies. Project I (Thrombin-Cleaved Osteopontin in AAA) will examine the role of thrombin-cleaved osteopontin and its regulation in AAA, and determine if measurements of specific cleaved forms of osteopontin will serve as useful biomarkers for predicting disease progression. Project II (Signature Protein Profile to Identify AAAs) will develop a custom antibody-based protein array to test whether distinct signature protein profiles can be identified that will correlate with AAA of different sizes, and whether changes in these profiles can predict disease progression and response to intervention. Project III (Hemodynamics in AAA Progression) will characterize the hemodynamics in the infrarenal aorta of patients with AAA, under both resting and exercise conditions, using MRI-based imaging techniques. We will examine how the shape, size, or vessel wall structure of the aortic aneurysm influence the hemodynamic parameters in AAA and test whether these changes in flow and vessel wall characteristics predict disease progression and response to intervention. Project IV (Evaluation of Exercise Therapy in Small AAA) is the key project in this SCCOR application. A prospective randomized trial will be carried out to test whether a supervised and sustained exercise program will reduce the rate of expansion of small AAA in patients. This clinical trial will anchor and connect all the other projects of this SCCOR. The proposed SCCOR will enable many accomplished investigators with complementary expertise to develop a coordinated and integrated approach to analysis, stratification and treatment of AAA disease, and fulfills the SCCOR objective of translating knowledge into clinical practice.