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novel strategies; predictive marker; prospective; response; small molecule; therapeutic target; translational study; unpublished works; vascular inflammation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，美国5-10％的男性和1-2％的女性在美国是65-79岁 与腹主动脉瘤（AAA）一起生活。由于AAA破裂，每年约有15,000人死亡。 由于缺乏其他良好益处的疗法，因此AAA的治疗方法仅限于手术干预。 尽管大多数AAA患者是不对称的，但由于破裂而导致的死亡风险大大增加，因为 AAAS扩展。对导致AAA进展的机制的见解将对 通过提供预测AAA扩展的新生物标志物，从而对AAA进行临床管理，从而有 主动脉破裂以及干预的新策略。我们实验室最近发表的发现 提供AAA进展中血清淀粉样蛋白A（SAA）详细评估的动力：1）SAA缺乏症 减弱鼠标模型中的AAA； 2）在小鼠中，SAA存在于AAA中 降解，巨噬细胞浸润和基质金属蛋白酶（MMP）活性； 3）可以检测到SAA 在人类AAA中。在未发表的工作中，我们还确定SAA会影响IL-1β和NLRP3表达，为 以及IL-1β分泌，在巨噬细胞中，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，这些发现是值得注意的 在小鼠的AAA发展中。这就是我们的中心假设是SAA激活NLRP3炎症体， 从而扩大局部炎症反应，从而增强病理组织重塑并促进 AAA进展。目标1：调查NLRP3炎症小体在SAA促进AAA的能力中的作用 老鼠。目标1a。使用缺乏各种炎性组成分的小鼠（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是否取决于NLRP3 炎症。我们还将研究小分子阴离子磺酸盐是否可以阻止这种治疗 SAA在组织中的沉积有效减少小鼠的AAA。目标1B。使用巨噬细胞培养物， 我们将调查是否归因于SAA的任何已知生物活性，包括活性氧 物种产生或与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促进已建立的AAA的进展的假设。目标2a。 我们的方法是在小鼠的生活中以特定时间间隔暂时增加SAA的表达。 通过使用病毒载体和诱导转化，Angii输注的过程。作为一个完整 方法，SAA表达将使用反义寡核苷酸抑制。 SAA对指数的影响 将确定AAA进展和主动脉射击和重塑的序列。目标2B。调查 SAA和炎性体激活在人AAA中的潜在作用，血浆SAA，IL-1β之间的关系 并且将在前瞻性N-TA3CT试验中确定人类的AAA扩张率。这些研究 拥有确定AAA临床管理的新策略的潜力。