Correlation of MMP activity with anatomic changes in the ruptured AAA wall

描述（由申请方提供）：腹主动脉瘤（AAA）是一种致死性疾病，随着人口老龄化，会对公共卫生产生重大影响。AAA破裂与一致的高死亡率（80%）相关。虽然在了解AAA发展的病理生理学和降低择期AAA修复术的死亡率方面取得了重大进展，但对导致AAA破裂的一系列事件知之甚少。在临床上，多种危险因素与破裂相关，包括主动脉直径，以及慢性阻塞性肺疾病和高血压的共存。虽然已经开发了三种当代动物模型来检查与AAA发展相关的分子事件，但很少有模型可用于研究与AAA破裂相关的事件。从人类的观察队列中，初步数据表明丝氨酸蛋白酶（例如纤溶酶原激活剂tPA和uPA）超过其抑制剂，在主动脉壁的特定位置激活金属蛋白酶（MMP 2和9），促进胶原破坏和随后的主动脉壁破裂。建立AAA破裂模型并确定主动脉破裂的潜在机制对于更好地确定人类风险至关重要，将是本研究的重点。使用主动脉壁和血清生物标志物，以及解剖和功能成像技术（超声，FDG-PET扫描和放射自显影，MRA）了解主动脉壁破裂前和破裂前即刻发生的时间差异，将使我们能够开发新的转化方法来治疗主动脉破裂前的患者。 公共卫生相关性：腹主动脉瘤（AAA）是一种致死性疾病，随着人口老龄化和有发生AAA风险的患者数量增加，会产生重大的公共卫生后果。临床上，AAA很重要，因为其破裂与非常高的死亡风险相关。这项研究将允许开发非侵入性成像技术，可用于在必须进行紧急手术之前确定AAA何时易于破裂或夹层。

DESCRIPTION (provided by applicant): Abdominal aortic aneurysm (AAA) is a lethal disease, with significant public health ramifications as the population ages. AAA rupture is associated with a uniformly high mortality rate (80%). While significant strides have been made in understanding the pathophysiology of AAA development and in decreasing the mortality of elective AAA repair, little is known about the series of events leading to AAA rupture. Clinically, multiple risk factors are associated with rupture, including aortic diameter, as well as the coexistence of chronic obstructive pulmonary disease and hypertension. While three contemporary animal models have been developed to examine the molecular events associated with AAA development, few models are available to study the events associated with AAA rupture. From observational cohorts in humans, preliminary data suggests that serine proteases (e.g. plasminogen activators tPA and uPA), in excess of their inhibitors, activate metalloproteinase's (MMP2 and 9) at specific locations in the aortic wall promoting collagen destruction and subsequent aortic wall rupture. Establishing a model of AAA rupture and defining the mechanisms underlying aortic rupture are critical to better define the risk in humans and will be the focus of the present investigation. Understanding temporal differences that occur in the aortic wall leading to and immediately prior to rupture using aortic wall and serum biomarkers, as well as anatomic and functional imaging techniques (ultrasound, FDG-PET scanning and autoradiographs, MRA) will allow us to develop new translational approaches to treat patients prior to aortic rupture. PUBLIC HEALTH RELEVANCE: Abdominal aortic aneurysm (AAA) is a lethal disease, with significant public health ramifications as the population ages and the number of patients at risk for development of AAAs increases. Clinically, AAAs are important because their rupture is associated with a very high risk of death. This study will allow for the development of non-invasive, imaging techniques that can be used to determine when AAAs are prone to rupture or dissection before emergency surgery must be performed.