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: 8312534
• 负责人: RONALD L DALMAN
• 金额: $ 23.83万
• 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 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8312534
• 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.

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。

项目成果

CCR2 inhibition sequesters multiple subsets of leukocytes in the bone marrow.

• DOI: 10.1038/srep11664
• 发表时间: 2015-07-24
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Fujimura N;Xu B;Dalman J;Deng H;Aoyama K;Dalman RL
• 通讯作者: Dalman RL

Hypoxia-inducible factor 1 in clinical and experimental aortic aneurysm disease.

临床和实验性主动脉瘤疾病中缺氧诱导因子1。

• DOI: 10.1016/j.jvs.2017.09.030
• 发表时间: 2018-11
• 期刊: Journal of vascular surgery
• 影响因子: 4.3
• 作者: Wang W;Xu B;Xuan H;Ge Y;Wang Y;Wang L;Huang J;Fu W;Michie SA;Dalman RL
• 通讯作者: Dalman RL

Peptide inhibitor of CXCL4-CCL5 heterodimer formation, MKEY, inhibits experimental aortic aneurysm initiation and progression.

• DOI: 10.1161/atvbaha.112.300329
• 发表时间: 2013-04
• 期刊: Arteriosclerosis, thrombosis, and vascular biology
• 作者: Iida Y;Xu B;Xuan H;Glover KJ;Tanaka H;Hu X;Fujimura N;Wang W;Schultz JR;Turner CR;Dalman RL
• 通讯作者: Dalman RL

Efficacy and mechanism of angiotensin II receptor blocker treatment in experimental abdominal aortic aneurysms.

• DOI: 10.1371/journal.pone.0049642
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Iida Y;Xu B;Schultz GM;Chow V;White JJ;Sulaimon S;Hezi-Yamit A;Peterson SR;Dalman RL
• 通讯作者: Dalman RL

Treatment With Small Molecule Inhibitors of Advanced Glycation End-Products Formation and Advanced Glycation End-Products-Mediated Collagen Cross-Linking Promotes Experimental Aortic Aneurysm Progression in Diabetic Mice.

• DOI: 10.1161/jaha.122.028081
• 发表时间: 2023-05-16
• 期刊: JOURNAL OF THE AMERICAN HEART ASSOCIATION
• 影响因子: 5.4
• 作者: Li, Yankui;Zheng, Xiaoya;Guo, Jia;Samura, Makoto;Ge, Yingbin;Zhao, Sihai;Li, Gang;Chen, Xiaofeng;Shoji, Takahiro;Ikezoe, Toru;Miyata, Masaaki;Xu, Baohui;Dalman, Ronald L. L.
• 通讯作者: Dalman, Ronald L. L.