Mechanistic studies of disease progression in aortic aneurysms

腹主动脉瘤（AAA）是退伍军人中的一种常见疾病， 吸烟者和负责10，000记录的死亡每年在美国。AAA治疗仍然存在 仅限于大动脉瘤的手术或血管内修复。缺乏有效的药物治疗反映了 关于AAA分子机制的知识存在差距，缺乏可靠的工具， 评价血管壁生物学和监测体内治疗效果。若干矩阵 包括MMP-12在内的金属蛋白酶（MMP）在人AAA中上调，并且许多MMP与人AAA中的MMP-12相关。 与AAA的发展相联系。弹性蛋白降解是动脉瘤的一个关键特征，MMP-12被认为是 这种情况下的主要弹性蛋白酶关于MMP-12在动脉瘤中的作用有相互矛盾的数据 发展和新出现的信息指出MMP-12在炎症中的抗炎和促炎功能， 炎症性疾病这与我们的初步数据相结合，提出了一个有趣的假设，MMP- 12在动脉瘤中起双重作用：通过抑制中性粒细胞， 募集到血管壁，并通过增强动脉瘤的扩张和破裂来促进已建立的动脉瘤的扩张和破裂。 血管壁炎症。在这里，我们介绍了新的分子成像技术，用于高分辨率跟踪 血管壁炎症和MMP/MMP-12成像，与选择性抑制剂和 a）研究MMP/MMP-12激活的时间和空间模式， 与AAA发生、进展和破裂的关系;和B）探讨MMP-12在动脉瘤中的作用。 血管重塑将被跟踪高分辨率多模态分子和结构成像 随后在两种互补的小鼠模型中进行组织形态计量学分析，即血管紧张素II诱导的 和氯化钙诱发的动脉瘤血管壁生物学， 对治疗的反应，以及动脉瘤扩张和破裂将通过系列成像在 同样的动物。MMP-12基因缺失和MMP-12抑制对动脉瘤发展的影响， 将讨论已建立动脉瘤的演变。结合起来，这些研究将解决新的方面， 动脉瘤病理生物学，在临床前模型中验证新的治疗靶点，并建立新的成像 评价动脉瘤血管壁生物学的方法。最终，这将改善 管理AAA患者（可能还有其他血管疾病）;并降低相关发病率， 死亡率和医疗费用。

Abdominal aortic aneurysm (AAA), a prevalent disease amongst veterans, affects more than 1 in 9 smokers and is responsible for 10,000 documented deaths every year in the US. AAA treatment remains limited to surgical or endovascular repair for large aneurysms. This lack of an effective medical therapy reflects existing gaps in knowledge regarding the molecular mechanisms of AAA, and lack of reliable tools for evaluating vessel wall biology and monitoring therapeutic effectiveness in vivo. Several matrix metalloproteinases (MMPs), including MMP-12 are upregulated in human AAA, and a number of MMPs have been linked to AAA development. Elastin degradation is a key feature of aneurysm and MMP-12 is considered the primary elastase in this setting. There are conflicting data regarding the role of MMP-12 in aneurysm development and emerging information point to both anti- and pro-inflammatory functions for MMP-12 in inflammatory disorders. This in conjunction with our preliminary data raise the intriguing hypothesis that MMP- 12 plays a dual role in aneurysm: inhibiting early stage aneurysm development through inhibition of neutrophil recruitment to the vessel wall, and promoting expansion and rupture of established aneurysms by enhancing vessel wall inflammation. Here, we introduce novel molecular imaging techniques for high resolution tracking of vessel wall inflammation and MMP/MMP-12 imaging, which in conjunction with selective inhibitors and knockout mice will be used to a) investigate the temporal and spatial pattern of MMP/MMP-12 activation in relation to AAA development, progression and rupture; and b) address the role of MMP-12 in aneurysm. Vascular remodeling will be tracked with high resolution multimodality molecular and structural imaging followed by histomorphometric analysis in two complementary murine models, namely angiotensin II-induced and calcium chloride-induced aneurysms. The temporal and spatial relationship between vessel wall biology, response to therapy, and aneurysm expansion and rupture will be addressed through serial imaging in the same animal. The effects of MMP-12 gene deletion and MMP-12 inhibition on aneurysm development, and evolution of established aneurysms will be addressed. Combined, these studies will address novel aspects of aneurysm pathobiology, validate novel therapeutic targets in preclinical models, and establish novel imaging approaches for evaluation of vessel wall biology in aneurysms. Ultimately, this should lead to improved management of patients with AAA (and possibly other vascular diseases); and reduce related morbidity, mortality, and healthcare costs.