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

MMP 活性与破裂 AAA 壁解剖变化的相关性

• 批准号: 8195887
• 负责人: Sean Jason English
• 金额: $ 4.69万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-31 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8195887
• 关键词: Abdominal Aortic Aneurysm; Age; Anatomy; Aneurysm; Animal Model; Animals; Aorta; Aortic Rupture; Autoradiography; Biological Markers; Caliber; Cessation of life; Chronic Obstructive Airway Disease; Collagen; Data; Development; Disease; Dissection; Elastases; Emergency Situation; Event; Functional Imaging; Functional disorder; Human; Imaging Techniques; Immunohistochemistry; Inflammatory Response; Infusion procedures; Investigation; Laboratories; Location; MMP2 gene; Matrix Metalloproteinases; Metabolic; Metalloproteases; Modeling; Molecular; Operative Surgical Procedures; Patients; Perfusion; Phenotype; Plasminogen Activator; Plasminogen Activator Inhibitor 1; Population; Positron-Emission Tomography; Public Health; Pulmonary Hypertension; Rattus; Relative (related person); Risk; Risk Factors; Rupture; Ruptured Abdominal Aortic Aneurysm; Ruptured Aortic Aneurysms; Scanning; Series; Serine Protease; Serum; Testosterone; Tissues; Ultrasonography; base; cohort; fluorodeoxyglucose positron emission tomography; high risk; inhibitor/antagonist; male; mortality; public health relevance; repaired; research study; translational approach

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.

描述（由申请人提供）：腹主动脉瘤（AAA）是一种致命疾病，随着人口老龄化，对公共健康产生重大影响。 AAA 破裂与较高的死亡率 (80%) 相关。虽然在了解 AAA 发展的病理生理学和降低选择性 AAA 修复的死亡率方面已经取得了重大进展，但对导致 AAA 破裂的一系列事件却知之甚少。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病和高血压的共存。虽然已经开发了三种当代动物模型来研究与 AAA 发育相关的分子事件，但很少有模型可用于研究与 AAA 破裂相关的事件。人类观察组的初步数据表明，丝氨酸蛋白酶（例如纤溶酶原激活剂 tPA 和 uPA）超过其抑制剂，会激活主动脉壁特定位置的金属蛋白酶（MMP2 和 9），促进胶原蛋白破坏和随后的主动脉壁破裂。建立 AAA 破裂模型并定义主动脉破裂的机制对于更好地确定人类风险至关重要，并将成为当前研究的重点。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）了解主动脉壁导致破裂和破裂前发生的时间差异，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) 是一种致命疾病，随着人口老龄化和有发生 AAA 风险的患者数量增加，对公共卫生产生重大影响。在临床上，AAA 很重要，因为它们的破裂与极高的死亡风险相关。这项研究将有助于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 何时容易破裂或剥离。