Impact of the micromechanical environment on inflammation in AAA progression

微机械环境对 AAA 进展中炎症的影响

基本信息

批准号：
8900331
负责人：
Naomi C Chesler
金额：
$ 18.53万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8900331
关键词：
Abdominal Aortic Aneurysm Affect Aging Aneurysm Angiotensin II Animals Anti-Inflammatory Agents Anti-inflammatory Aorta Apolipoprotein E Apoptotic Arteries Behavior Biological Assay Biomechanics Blood Vessels Breeding Cause of Death Cell Culture Techniques Cells Collagen Collagen Fiber Data Defect Deposition Development Diagnosis Disease Down-Regulation Elastases Elastin Elderly Environment Excision Extracellular Matrix Fibroblasts Flow Cytometry Foundations Functional disorder Future Gel Health Heating Histologic Human Characteristics In Vitro Infiltration Inflammation Inflammatory Inflammatory Infiltrate Inflammatory Response Infusion procedures Knowledge Lipoproteins Macrophage Colony-Stimulating Factor Mechanics Mediating Modeling Mouse Strains Mus Mutant Strains Mice Operative Surgical Procedures Pathologic Processes Patients Peptide Hydrolases Perfusion Pharmacologic Substance Play Population Property Risk Risk Factors Rupture Ruptured Aneurysm Smooth Muscle Myocytes Source Testing Therapeutic Tissues Transgenic Mice United States Vascular Diseases Work age related base crosslink cytokine cytotoxic design disability drug development expectation in vitro testing in vivo insight macrophage monocyte mutant novel prevent vascular inflammation

项目摘要

DESCRIPTION (provided by applicant): Aging is the most important yet least understood risk factor for abdominal aortic aneurysm (AAA), a common, progressive vascular disease with high lethality. The vascular extracellular matrix (ECM) changes with aging, characterized by stiffer and less organized collagen fibers. We hypothesize that these age-related ECM changes predispose older arteries to aneurysm not only by altering vessel mechanical properties but also by influencing the functions of infiltrating inflammatory cells. In this R21, we propose to specifically test how age-related collagen changes affect the inflammatory response during the course of aneurysm development using the transgenic mouse strain Col1a1. The homozygous mutant animals (Col1a1R/R) have been shown to display excessive collagen accumulation and subsequent ECM stiffening as well as exacerbated aneurysm formation. Two Specific Aims are proposed. In Aim 1, we will test whether ECM stiffening accelerates AAA progression and intensifies vascular inflammation by subjecting Col1a1 mutant and wildtype (Col1a1+/+) mice to AAA induction via intraluminal perfusion with elastase (AAA) or heat-inactivated elastase (sham). This so called elastase model is widely accepted for its duplication of major pathological characteristics of human AAAs. We will focus on macrophage-mediated inflammation because macrophages are the predominant type of inflammatory cells found in aneurysmal aorta and are thought to be the major source of elastin degrading proteases. In addition to macrophage recruitment, we will examine macrophage differentiation with the expectation that ECM stiffening facilitates differentiation of the proinflammatory subtype or M1 macrophages or/and suppresses differentiation of the anti-inflammatory subtype or M2 macrophages. Currently, how macrophage subtypes are distributed in aneurysmal tissue and how subtype differentiation may be affected by aging ECM is completely unknown. In Aim 2, we propose culture monocytes (the precursors of macrophages) from wildtype or mutant mice in collagen gels of increasing stiffness to study how collagen-mediated ECM stiffening influences the recruitment and differentiation of inflammatory cells. The results obtained from this study will provide a new concept in understanding aging-associated AAA formation and lay a foundation for future mechanistic studies and drug development. Therefore, our work is significant, novel, and translational.

描述（由申请人提供）：衰老是腹主动脉瘤 (AAA) 最重要但了解最少的危险因素，腹主动脉瘤是一种常见的进行性血管疾病，具有高致死率。血管细胞外基质 (ECM) 随着年龄的增长而变化，其特点是胶原纤维变得更硬、组织更差。我们推测，这些与年龄相关的 ECM 变化不仅通过改变血管机械特性，而且还通过影响浸润炎症细胞的功能，使老年动脉易于形成动脉瘤。在此 R21 中，我们建议使用转基因小鼠品系 Col1a1 专门测试与年龄相关的胶原蛋白变化如何影响动脉瘤发展过程中的炎症反应。纯合突变动物 (Col1a1R/R) 已被证明表现出过度的胶原蛋白积累和随后的 ECM 硬化以及加剧的动脉瘤形成。提出了两个具体目标。在目标 1 中，我们将通过腔内灌注弹性蛋白酶 (AAA) 或热灭活弹性蛋白酶（假手术）对 Col1a1 突变型和野生型 (Col1a1+/+) 小鼠进行 AAA 诱导，测试 ECM 硬化是否会加速 AAA 进展并加剧血管炎症。这种所谓的弹性蛋白酶模型因其复制人类 AAA 的主要病理特征而被广泛接受。我们将重点关注巨噬细胞介导的炎症，因为巨噬细胞是动脉瘤主动脉中发现的炎症细胞的主要类型，并且被认为是弹性蛋白降解蛋白酶的主要来源。除了巨噬细胞募集之外，我们还将检查巨噬细胞分化，期望 ECM 硬化促进促炎亚型或 M1 巨噬细胞的分化或/和抑制抗炎亚型或 M2 巨噬细胞的分化。目前，巨噬细胞亚型如何在动脉瘤组织中分布以及老化 ECM 如何影响亚型分化是完全未知的。在目标 2 中，我们建议在硬度增加的胶原凝胶中培养来自野生型或突变型小鼠的单核细胞（巨噬细胞的前体），以研究胶原介导的 ECM 硬化如何影响炎症细胞的招募和分化。这项研究获得的结果将为理解衰老相关的AAA形成提供新的概念，并为未来的机制研究和药物开发奠定基础。因此，我们的工作具有重要意义、新颖性和转化性。