Critical Role of Inflammatory Macrophages in AAA Pathogenesis

描述(申请人提供)：腹主动脉瘤(AAA)是美国成年人的一种常见且致命的疾病。在几个月到几年的过程中，AAA的渐进性扩大会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，这会带来相当大的发病率和/或需要持续监测和定期重新干预。先前试图确定用于医疗干预的特定介体或途径靶点，但并未转化为有效的临床治疗。作为动脉瘤变性的最终共同效应细胞，活化的浸润性巨噬细胞代表了一种新的、潜在的高效抑制治疗的靶点。叶酸受体2(FR2)的表面表达识别激活的巨噬细胞亚群，被发现促进包括动脉粥样硬化、关节炎和狼疮在内的各种炎症条件。尽管我们最近证实在实验性动脉瘤中存在大量FR2阳性的巨噬细胞，但这些细胞在AAA发病机制中可能发挥的作用仍不清楚。根据现有的支持信息，我们的基本假设是表达FR2的巨噬细胞调节AAA的启动和进展。为了推进这一假设，我们提出了以下具体目标：1.量化AAA疾病进展过程中表达FR2的壁状巨噬细胞的位置、时间和功能相关性。2.明确表达FR2的巨噬细胞在实验性AAA中的功能后果。利用已建立和补充的实验性AAA病小鼠模型，我们将使用免疫组织化学技术来分析FR2阳性巨噬细胞在动脉瘤发展过程中的动力学和功能状态。我们将通过PAN和选定的巨噬细胞耗竭研究来分析这一激活的巨噬细胞亚群在实验性动脉瘤开始之前和之后的功能意义。确认激活的巨噬细胞在AAA病中的发病意义将有助于将新出现的抗FR2治疗策略迅速转化为有效的非手术方法抑制动脉瘤。

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.