Metabolic Syndrome & Pathobiology of Aortic Aneurysms

代谢综合征

• 批准号: 7140852
• 负责人: Robert W. Thompson
• 金额: $ 44.83万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7140852
• 关键词: C reactive protein; abdomen; aneurysm; aorta aneurysm; ataxia telangiectasia; biomarker; carotid artery; chloroquine; comorbidity; connective tissue; hematopoietic stem cells; human subject; inflammation; interleukin 6; metabolic syndrome; metalloendopeptidases; pathologic process; patient oriented research; stem cells

Since the metabolic syndrome is present in about a quarter of American adults and almost half of those over the age of 60, it is not surprising that nearly 50% of patients with abdominal aortic aneurysms (AAAs) fulfill the criteria for this syndrome. However, it is surprising that essentially nothing is known about how the presence of this syndrome affects the clinical manifestations of AAAs. AAAs are a common form of vascular disease characterized by chronic aortic wall inflammation and connective tissue destruction, depletion of medial smooth muscle cells, and impaired connective tissue repair. Patients with AAAs exhibit aortic tissue production and elevated circulating levels of pro-inflammatory proteins that may serve as biomarkers of disease activity. Reparative biological processes, such as recruitment of bone marrow-derived vascular progenitor cells and neovascularization, might be capable of stabilizing aneurysm tissue. Many of these events are recapitulated in mouse models of AAAs. Many of the same pro-inflammatory proteins that circulate in patients with AAAs are also increased in people with the metabolic syndrome. This project will test the hypothesis that the presence of the metabolic syndrome adversely impacts the clinical course of people with AAAs. Several pro-inflammatory mediators affecting AAA biology may also be affected through signaling pathways triggered by ATM (Ataxia Telangiectasia Mutated) and data from Project 1 show that this protein can be activated by chloroquine. We will also test the hypothesis that the ATM pathway modulates inflammation to affect anuerysm formation. We will address the following aims: 1-Determine if the presence of metabolic syndrome in humans influences inflammatory markers and a clinically relevant outcome (persistent aneurysm expansion following endovascular aneurysm repair). 2-Establish if the presence of metabolic syndrome in humans influences aortic tissue recruitment and circulating levels of vascular progenitor cells capable of connective tissue repair. 3-Evaluate if ATM deficiency in mice affects the development of experimental AAAs and if ATM activation with chloroquine can suppress experimental AAAs. This project has the potential to transform the care of people with the metabolic syndrome by establishing the mechanisms by which this disorder may affect clinical outcomes following surgical repair of aneurysms.

由于代谢综合征存在于大约四分之一的美国成年人和几乎一半的人中， 在60岁以上的患者中，近50%的腹主动脉瘤（AAA）患者 符合该综合征的标准。然而，令人惊讶的是，基本上不知道如何 该综合征的存在影响AAAs的临床表现。 AAA是以慢性主动脉壁炎症为特征的血管疾病的常见形式， 结缔组织破坏、中膜平滑肌细胞耗竭和结缔组织受损 修复. AAA患者表现出主动脉组织生成和促炎性循环水平升高， 这些蛋白质可以作为疾病活动的生物标志物。修复性生物过程，如 骨髓来源的血管祖细胞的募集和新血管形成，可能能够 稳定动脉瘤组织这些事件中的许多在AAAs的小鼠模型中重现。许多 在AAA患者体内循环的相同促炎蛋白质也在AAA患者体内增加。 代谢综合征这个项目将测试的假设，即代谢综合征的存在， 对AAA患者的临床进程产生不利影响。几种促炎介质影响 AAA生物学也可能通过ATM（共济失调毛细血管扩张症）触发的信号通路受到影响 突变）和项目1的数据表明，这种蛋白质可以被氯喹激活。我们还将测试 ATM通路调节炎症以影响动脉瘤形成的假说。 我们将致力于实现以下目标： 1-确定人类代谢综合征的存在是否会影响炎症标志物， 临床相关结局（动脉瘤腔内修复术后持续性动脉瘤扩张）。 2-确定人类代谢综合征的存在是否影响主动脉组织募集， 能够修复结缔组织的血管祖细胞的循环水平。 3-评价小鼠中ATM缺乏是否影响实验性AAA的形成，以及ATM激活是否 可以抑制实验性的AAAs。 该项目有可能通过建立一个新的代谢综合征患者的护理模式， 这种疾病可能影响动脉瘤手术修复后临床结局的机制。