AAA Disease: Mechanism, Stratification and Treatment

描述(由申请人提供)： 腹主动脉瘤(AAA)是一种常见的、病态的、经常致命的美国老年人疾病。AAA疾病的主要临床挑战包括：1)有效的非手术治疗以防止早期疾病的进展，以及2)有效的生物标志物或有效的成像指标来监测疾病的活动性和指导对小动脉瘤的抑制性药物治疗。基于大量先前证据表明，可变的主动脉血流和壁切应力条件调节血管炎症，本SCCOR建议：1)识别和验证用于AAA疾病分层的新的生物标记物和成像策略，2)测试运动疗法抑制小AAA的能力，以及3)研究实验性AAA演变过程中存在的关键分子和细胞事件，以识别和改进新的治疗策略。项目I(凝血酶裂解的骨桥蛋白在AAA中)将研究凝血酶裂解的骨桥蛋白在AAA中的作用及其调节，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记物。项目II(识别AAA的标志性蛋白质图谱)将开发一个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的AAA相关的不同的标志性蛋白质图谱，以及这些图谱的变化是否可以预测疾病的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的成像技术来表征AAA患者在静息和运动条件下的肾下主动脉的血流动力学。我们将研究主动脉瘤的形状、大小或管壁结构如何影响AAA的血流动力学参数，并测试这些血流和管壁特征的变化是否可以预测疾病的进展和介入治疗的反应。项目IV(运动疗法在小AAA中的评估)是SCCOR应用中的关键项目。将进行一项前瞻性随机试验，以测试有监督的持续锻炼计划是否会降低患者小型AAA的扩张率。这项临床试验将固定和连接该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。

DESCRIPTION (provided by applicant): 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.