Critical Role of Inflammatory Macrophages in AAA Pathogenesis

描述（由申请人提供）：腹主动脉瘤（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进行性扩大导致灾难性破裂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/或需要持续监测和定期再干预。先前尝试鉴定用于医学干预的特定介质或途径靶标尚未转化为有效的临床疗法。活化的浸润性巨噬细胞作为淋巴细胞变性的最终共同效应细胞，代表了抑制治疗的新的和潜在的高效靶点。叶酸受体2（FR 2）的表面表达鉴定了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性病症的活化巨噬细胞的子集。虽然我们最近证实了FR 2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发病机制中可能发挥的作用仍然未知。基于现有的支持信息，我们的基本假设是表达FR 2的巨噬细胞调节AAA的发生和进展。为了实现这一假设，我们提出了以下具体目标：1。在AAA疾病进展过程中，量化表达FR 2的壁巨噬细胞的位置、时间和功能相关性。 2.定义实验性AAA中表达FR 2的巨噬细胞耗竭的功能后果。使用实验性AAA疾病的已建立和互补的小鼠模型，我们将采用免疫组织化学技术来分析动脉瘤发展过程中FR 2阳性巨噬细胞的动力学和功能状态。我们将通过在实验性动脉瘤形成之前和之后的泛巨噬细胞和选择性巨噬细胞耗竭研究来分析该活化巨噬细胞亚群的功能意义。证实活化巨噬细胞在AAA疾病中的发病学意义将有助于将新兴的抗FR 2治疗策略快速转化为有效的动脉瘤抑制非手术方法。 公共卫生相关性：腹主动脉瘤（AAA）是一种常见的、病态的和经常致命的疾病。在研究活化的巨噬细胞（由叶酸受体表达状态定义）如何影响动脉瘤进展的过程中，我们希望发现新的治疗策略来限制早期AAA疾病的进展，并在此过程中改善数百万美国人的健康和福祉。

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. PUBLIC HEALTH RELEVANCE: Abdominal aortic aneurysm (AAA) is a common, morbid and frequently lethal disease. In the course of investigating how activated macrophages (as defined by folate receptor expression status) influence aneurysm progression, we hope to discover novel treatment strategies to limit progression of early AAA disease and, in the process, improve the health and well-being of millions of Americans.