Critical Role of Inflammatory Macrophages in AAA Pathogenesis

炎症巨噬细胞在 AAA 发病机制中的关键作用

• 批准号: 8179456
• 负责人: RONALD L DALMAN
• 金额: $ 19.88万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-08 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8179456
• 关键词: Abdominal Aortic Aneurysm; Adult; American; Aneurysm; Aortic Aneurysm; Aortic Rupture; Arthritis; Atherosclerosis; Caliber; Cells; Cessation of life; Chronic; Chronic Disease; Clinical; Collagen; Confocal Microscopy; Development; Disease; Disease Management; Disease Progression; Effector Cell; Elastin; Experimental Models; Failure; Fluorescence-Activated Cell Sorting; Frequencies; Functional disorder; Health; Human; ITGAM gene; Immigration; Immunofluorescence Immunologic; Immunotoxins; Inflammation; Inflammatory; Intervention; Intracellular Transport; Kinetics; Learning; Leukocytes; Ligands; Location; Lupus; Medial; Mediating; Mediator of activation protein; Medical; Methods; Morbidity - disease rate; Mus; Operative Surgical Procedures; Pathogenesis; Pathway interactions; Peptide Hydrolases; Personal Satisfaction; Play; Population; Predisposition; Process; Production; Reactive Oxygen Species; Risk; Role; Rupture; Specimen; Structure; Sudden Death; Surface; Surgical Management; Suspension substance; Suspensions; Techniques; Testing; Therapeutic; Time; Translating; Translations; Vascular Diseases; abdominal aorta; attenuation; base; clinically relevant; cytokine; folate-binding protein; functional status; improved; macrophage; novel; premature; prevent; receptor; receptor expression; repaired; research study; treatment strategy

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.

描述（由申请人提供）：腹主动脉瘤（AAA）是美国成年人的一种常见且致命的疾病。经过数月至数年的时间，AAA 逐渐增大，导致因灾难性破裂而猝死的风险不断增加。目前，只能通过及时的手术修复来预防破裂，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。先前尝试确定医疗干预的特定介质或途径目标尚未转化为有效的临床疗法。作为动脉瘤变性的最终常见效应细胞，活化的浸润性巨噬细胞代表了抑制治疗的一种新颖且潜在高效的靶标。叶酸受体 2 (FR2) 的表面表达可识别活化巨噬细胞的子集，这些巨噬细胞可促进各种炎症状况，包括动脉粥样硬化、关节炎和狼疮。尽管我们最近证实实验性动脉瘤中存在大量 FR2 阳性巨噬细胞，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 的起始和进展。为了实现这一假设，我们提出以下具体目标： 1. 量化 AAA 疾病进展期间表达 FR2 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 FR2 的巨噬细胞耗竭的功能后果。利用已建立的补充实验性 AAA 疾病小鼠模型，我们将采用免疫组织化学技术来分析动脉瘤发展过程中 FR2 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发生之前和之后的泛巨噬细胞耗竭研究和选择性巨噬细胞耗竭研究来分析这部分活化巨噬细胞的功能意义。确认激活的巨噬细胞在 AAA 疾病中的发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非手术抑制动脉瘤方法。 公众健康相关性：腹主动脉瘤 (AAA) 是一种常见、病态且常常致命的疾病。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。