Serum Amyloid A, Inflammasome Activation, and Abdominal Aortic Aneurysms

血清淀粉样蛋白 A、炎症小体激活和腹主动脉瘤

• 批准号: 9213910
• 负责人: FREDERICK C. DE BEER
• 金额: $ 52.63万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9213910
• 关键词: Abdominal Aortic Aneurysm; Acute; Age-Years; Angiotensin II; Antisense Oligonucleotides; Aortic Rupture; Apolipoprotein E; Attenuated; Biological; Biological Markers; Blood Vessels; CASP1 gene; CCL2 gene; Caring; Cell Culture Techniques; Cells; Cessation of life; Chronic; Clinical Management; Data; Deposition; Development; Elastin; Evaluation; Event; Generations; High Density Lipoproteins; Human; Infection; Infiltration; Inflammasome; Inflammation; Inflammation Mediators; Inflammatory Response; Infusion procedures; Injury; Interleukin-1 beta; Intervention; Laboratories; Liver; Matrix Metalloproteinases; Medial; Mediating; Mus; Operative Surgical Procedures; Pathologic; Patients; Plasma; Proteins; Publications; Publishing; Reactive Oxygen Species; Risk; Role; Rupture; Ruptured Abdominal Aortic Aneurysm; Serum amyloid A protein; Signal Transduction; Smooth Muscle Myocytes; Staining method; Stains; Symptoms; TNF gene; Testing; Tissues; Transgenes; United States; Viral Vector; Woman; adeno-associated viral vector; base; effective therapy; human old age (65+); indexing; innovation; insight; macrophage; men; mouse model; novel; novel strategies; predictive marker; prospective; response; small molecule; therapeutic target; translational study; unpublished works; vascular inflammation

Recent estimates indicate that 5-10% of men and 1-2% of women 65-79 years of age in the United States are living with an abdominal aortic aneurysm (AAA). Approximately 15,000 will die each year due to AAA rupture. The treatment for AAA is limited to surgical intervention due to lack of other therapies with proven benefit. Although most patients with AAAs are asymptomatic, the risk of death due to rupture increases greatly as AAAs expand. Insights into mechanisms contributing to AAA progression would have a major impact on the clinical management of AAA by providing new biomarkers that predict AAA expansion and thus the risk for aortic rupture, as well as novel strategies for intervention. Recent published findings from our laboratory provide the impetus for a detailed evaluation of serum amyloid A (SAA) in AAA progression: 1) SAA deficiency attenuates AAA in a mouse model; 2) in mice, SAA is present in AAA in regions with substantial elastin degradation, macrophage infiltration, and matrix metalloproteinase (MMP) activity; and 3) SAA can be detected in human AAA. In unpublished work, we also determined that SAA induces IL-1β and NLRP3 expression, as well as IL-1β secretion, in macrophages, consistent with priming and activation of the NLRP3 inflammasome. These findings are notable, given the recent recognition that NLRP3 inflammasome activation is a critical event in AAA development in mice. Thus, our central hypothesis is that SAA activates the NLRP3 inflammasome, thereby amplifying local inflammatory responses that enhance pathological tissue remodeling and promote AAA progression. AIM 1: Investigate the role of the NLRP3 inflammasome in SAA's ability to promote AAA in mice. Aim 1a. Using mice deficient in various inflammasome components (NLRP3-/-, ASC-/-, caspase-1-/- mice) or IL-1β signaling (IL-1R-/- mice), we will determine whether SAA-mediated AAA is dependent on the NLRP3 inflammasome. We will also investigate whether small-molecule anionic sulphonates, a treatment that blocks the deposition of SAA in tissues, is effective in reducing AAA in mice. Aim 1b. Using macrophage cell cultures, we will investigate whether any of the known biological activities attributed to SAA, including reactive oxygen species generation or association with HDL, are involved in SAA-mediated NLRP3 inflammasome activation. AIM 2: To test the hypothesis that systemic SAA promotes the progression of an established AAA. Aim 2a. Our approach will be to transiently increase SAA expression in livers of mice at specific intervals during the course of AngII infusion through the use of viral vectors and an inducible transgene. As a complementary approach, SAA expression will be suppressed using antisense oligonucleotides. The impact of SAA on indices of AAA progression and aortic inflammation and remodeling will be determined. Aim 2b. To investigate the potential role of SAA and inflammasome activation in human AAA, the relationship between plasma SAA, IL-1β and the rate of AAA expansion in humans will be determined in the prospective N-TA3CT trial. These studies hold the potential for identifying new strategies for the clinical management of AAA.

最近的估计表明，在美国 65-79 岁的男性中，有 5-10% 的男性和 1-2% 的女性是 患有腹主动脉瘤 (AAA) 的患者每年约有 15,000 人会因 AAA 破裂而死亡。 由于缺乏其他已证实有效的治疗方法，AAA 的治疗仅限于手术干预。 尽管大多数 AAA 患者没有症状，但由于破裂导致死亡的风险大大增加 对促进 AAA 进展的机制的深入了解将对 AAA 产生重大影响。 通过提供新的生物标志物来预测 AAA 扩张，从而预测 AAA 的风险，从而对 AAA 进行临床管理 主动脉破裂，以及我们实验室最近发表的新的干预策略。 为详细评估 AAA 进展中的血清淀粉样蛋白 A (SAA) 提供动力：1) SAA 缺乏 减弱小鼠模型中的 AAA；2) 在小鼠中，SAA 存在于具有大量弹性蛋白的区域中 降解、巨噬细胞浸润和基质金属蛋白酶 (MMP) 活性；3) 可检测 SAA； 在人类 AAA 中，我们还确定 SAA 诱导 IL-1β 和 NLRP3 表达，如 以及巨噬细胞中 IL-1β 的分泌，与 NLRP3 炎性体的启动和激活一致。 鉴于最近认识到 NLRP3 炎性体激活是一个关键事件，这些发现值得注意 因此，我们的中心假设是 SAA 激活 NLRP3 炎症小体， 从而放大局部炎症反应，增强病理组织重塑并促进 AAA 进展。 目标 1：研究 NLRP3 炎症小体在 SAA 促进 AAA 的能力中的作用。 目标 1a. 使用缺乏各种炎性体成分的小鼠（NLRP3-/-、ASC-/-、caspase-1-/- 小鼠） 或 IL-1β 信号传导（IL-1R-/- 小鼠），我们将确定 SAA 介导的 AAA 是否依赖于 NLRP3 我们还将研究小分子阴离子磺酸盐是否可以阻断炎症小体。 使用巨噬细胞培养物，SAA 在组织中的沉积可有效减少小鼠体内的 AAA。 我们将调查是否有任何已知的生物活性归因于 SAA，包括活性氧 物种生成或与 HDL 的关联参与 SAA 介导的 NLRP3 炎性体激活。 目标 2：检验系统性 SAA 促进既定目标 2a 进展的假设。 我们的方法是在特定的时间间隔内暂时增加小鼠肝脏中 SAA 的表达。 通过使用病毒载体和诱导型转基因作为补充的 AngII 输注过程。 方法，使用反义寡核苷酸抑制SAA表达。 SAA对指数的影响。 将确定 AAA 进展和主动脉炎症和重塑的情况。 SAA和炎症小体激活在人AAA中的潜在作用，血浆SAA、IL-1β之间的关系 AAA 在人类中的扩张率将在前瞻性 N-TA3CT 试验中确定。 具有确定 AAA 临床管理新策略的潜力。