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

描述(由申请人提供)：腹主动脉瘤(AAA)是一种致命的疾病，随着人口老龄化，会对公共健康产生重大影响。AAA破裂与一致的高死亡率(80%)有关。虽然在理解腹主动脉发展的病理生理学和降低选择性腹主动脉修补术的死亡率方面已经取得了重大进展，但对导致腹主动脉破裂的一系列事件知之甚少。临床上，多种危险因素与破裂有关，包括主动脉直径，以及慢性阻塞性肺疾病和高血压的共存。虽然目前已经发展了三种动物模型来研究与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(如纤溶酶原激活剂tPA和uPA)超过其抑制物，激活主动脉壁特定位置的金属蛋白酶(MMP2和9)，促进胶原破坏和随后的主动脉壁破裂。建立腹主动脉破裂模型和确定主动脉破裂的机制对于更好地确定人类的风险至关重要，也将是目前研究的重点。通过使用主动脉壁和血清生物标记物，以及解剖和功能成像技术(超声、FDG-PET扫描和放射自显影，MRA)了解导致和紧接破裂前在主动脉壁发生的时间性差异，将使我们能够开发新的翻译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)是一种致命性疾病，随着人口老龄化和发展为腹主动脉瘤风险的患者数量增加，对公共健康具有重大影响。在临床上，AAA很重要，因为它们的破裂与非常高的死亡风险有关。这项研究将允许开发非侵入性的成像技术，在必须进行紧急手术之前，可以用来确定AAA何时容易破裂或夹层。

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.