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

基本信息

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
项目类别：
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

项目摘要

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）：腹主动脉瘤（AAA）是成年美国人的常见且致命的疾病。在几个月到数年的过程中，进步的AAA扩大导致灾难性破裂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，这对正在进行的监视和定期重新干预具有相当大的发病率和/或要求。先前尝试识别特定的介体或途径目标的医疗干预目标未转化为有效的临床疗法。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颖且潜在的高效抑制疗法靶标。叶酸受体2（FR2）的表面表达确定了一部分激活的巨噬细胞的子集，这些巨噬细胞促进了各种炎症条件，包括动脉粥样硬化，关节炎和狼疮。尽管我们最近确认FR2阳性巨噬细胞在实验性动脉瘤中存在很大数量，但这些细胞在AAA发病机理中的作用仍然未知。基于可用的支持信息，我们的基本假设表达FR2巨噬细胞调节AAA的启动和进展。为了提出这一假设，我们提出了以下具体目的：1。量化AAA疾病进展过程中表达FR2的壁画巨噬细胞的位置，时机和功能相关性。 2。定义了实验AAA中表达FR2的巨噬细胞耗竭的功能后果。使用实验性AAA疾病的既定和互补鼠模型，我们将采用免疫组织化学技术来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pan和选定的巨噬细胞耗尽研究在实验性动脉瘤开始之前和之后通过泛巨噬细胞耗竭研究来分析该激活巨噬细胞的功能意义。确认活化巨噬细胞在AAA疾病中的致病意义将有助于将新兴抗FR2治疗策略的快速转化为有效的非手术抑制方法。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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

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
影响因子：
0
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

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

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

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.

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