Critical Role of Inflammatory Macrophages in AAA Pathogenesis

描述（由申请人提供）：腹主动脉动脉瘤（AAA）是美国成年人常见的致命疾病。在数月至数年的过程中，AAA逐渐扩大，导致灾难性破裂导致猝死的风险不断增加。目前，破裂只能通过及时的手术修复来预防，这带来了相当大的发病率和/或需要持续的监测和定期的再干预。先前尝试确定特定的介质或途径目标的医疗干预尚未转化为有效的临床治疗。作为动脉瘤变性的最后一个常见效应细胞，活化的浸润性巨噬细胞代表了一种新的和潜在的高效抑制治疗靶点。叶酸受体2 （FR2）的表面表达确定了激活巨噬细胞的一个亚群，该亚群可促进各种炎症，包括动脉粥样硬化、关节炎和狼疮。尽管我们最近证实fr2阳性巨噬细胞在实验性动脉瘤中大量存在，但这些细胞在AAA发病机制中的作用尚不清楚。基于现有的支持信息，我们的基本假设是表达fr2的巨噬细胞调节AAA的发生和进展。为了实现这一假设，我们提出以下具体目标：1。量化AAA疾病进展过程中表达fr2的壁巨噬细胞的位置、时间和功能相关性。2. 确定fr2表达巨噬细胞耗损在实验性AAA中的功能后果。使用已建立的和互补的实验性AAA疾病小鼠模型，我们将采用免疫组织化学技术分析动脉瘤发育过程中fr2阳性巨噬细胞的动力学和功能状态。我们将通过实验动脉瘤发生前后的整体和选择性巨噬细胞消耗研究来分析这一激活巨噬细胞亚群的功能意义。确认活化的巨噬细胞在AAA疾病中的致病意义，将有助于将新兴的抗fr2治疗策略快速转化为有效的动脉瘤抑制非手术方法。

DESCRIPTION (provided by applicant): Abdominal aorta aneurysm (AAA) is a common and lethal disease of adult Americans. Progressive AAA enlargement, over the course of months to years, leads to ever-increasing risk of sudden death from catastrophic rupture. Currently, rupture can only be prevented by timely surgical repair, which carries considerable morbidity and/or requirements for ongoing surveillance and periodic re-intervention. Prior attempts to identify specific mediator or pathway targets for medical intervention have not translated to effective clinical therapies. As the final common effector cell for aneurysmal degeneration, the activated infiltrative macrophage represents a novel and potentially highly effective target for suppression therapy. Surface expression of the folate receptor 2 (FR2) identifies a subset of activated macrophages found to promote various inflammatory conditions including atherosclerosis, arthritis and lupus. Although we have recently confirmed that FR2-positive macrophages are present in significant numbers in experimental aneurysms, the role these cells may play in AAA pathogenesis remains unknown. Based on available supporting information, it is our fundamental hypothesis that FR2-expressing macrophages modulate AAA initiation and progression. To pursue this hypothesis, we propose the following Specific Aims: 1. Quantify the location, timing, and functional correlates of FR2-expressing mural macrophages during AAA disease progression. 2. Define the functional consequences of FR2-expressing macrophage depletion in experimental AAA. Using established and complementary murine models of experimental AAA disease, we will employ immunohistochemical techniques to analyze the kinetics and functional status of FR2-positive macrophages during aneurysm development. We will analyze the functional significance of this subset of activated macrophages by pan- and selected macrophage depletion studies prior to and following initiation of experimental aneurysms. Confirming the pathogenetic significance of activated macrophages in AAA disease will facilitate the rapid translation of emerging anti-FR2 therapeutic strategies to effective non-surgical methods of aneurysm suppression.