ADAR1 in abdominal aortic aneurysm

ADAR1 在腹主动脉瘤中的作用

基本信息

批准号：
9885780
负责人：
Shiyou Chen
金额：
$ 57.06万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
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：
2014-02-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9885780
关键词：
Abdominal Aortic Aneurysm Affect Aneurysm Antigens Aorta Arteries Attenuated Binding Biogenesis Blood Vessels Bone Marrow Transplantation Cardiovascular Diseases Collagen Core Facility Data Development Disease Elastin Environment Enzymes Equipment Extracellular Matrix Extracellular Matrix Degradation Extracellular Matrix Proteins Gelatinase A Goals Histologic Homeostasis Human Inflammation Inflammatory Knock-out Knockout Mice Knowledge Laboratories Lead MMP2 gene MMP9 gene Macrophage Activation Matrix Metalloproteinases Mediating MicroRNAs Molecular Mus Myelogenous NF-kappa B Outcome Patients Peptide Hydrolases Pharmacological Treatment Pharmacology Phenotype Play Positioning Attribute Prevention strategy Prevention therapy Production RNA RNA Editing Research Resources Ribonuclease III Role Signal Transduction Smooth Muscle Myocytes TIMP2 gene Techniques Testing Tissue Inhibitor of Metalloproteinases Tissues Treatment Efficacy Tunica Media Universities Vascular Smooth Muscle adenosine deaminase adenosine deaminase deficiency animal facility genetic approach improved in vivo injured knock-down loss of function mRNA Precursor mRNA Stability macrophage mouse model novel novel strategies novel therapeutics phenotypic biomarker pre-miRNA prevent pri-miRNA programs vascular inflammation

项目摘要

Summary/Abstract Abdominal aortic aneurysm (AAA) is a potentially lethal disease that lacks pharmacological treatment. Aortic wall inflammation and subsequent degradation of extracellular matrix (ECM) proteins, especially the elastin breakage, are the determining factors for the development of AAA. Vascular inflammation, particularly macrophage activation and inflammatory SMC phenotype, causes the production of proteolytic enzymes that disrupt ECM homeostasis leading to a weakened vessel wall and consequently AAA formation. However, there is a critical knowledge gap concerning the mechanism(s) or key factor(s) controlling both the vascular inflammation and the ECM dysregulation. Our exciting preliminary data indicate that adenosine deaminase acting on RNA 1 (ADAR1) plays a central role in the induction of inflammatory SMC phenotype, macrophage activation, and AAA formation. ADAR1 deficiency (ADAR1+/-) in mice significantly attenuates AAA formation (with decreased elastin breakage and improved artery wall integrity). ADAR1 knockdown or knockout also inhibits the inflammatory SMC phenotype and macrophage activation. Consequently, ADAR1 knockdown inhibits the expression of inflammation phenotype markers including matrix metalloproteinase-2 and 9 (MMP2/9) in SMCs while restoring contractile SMC markers. In addition, the classical MΦ activation is blocked when ADAR1 is deleted. Moreover, ADAR1 expression is associated with aneurysm formation in human patients. These data strongly support a novel hypothesis that ADAR1 induces inflammatory SMC phenotype and macrophage activation, leading to vascular inflammation, elastin breakage, and consequently AAA formation. Using primary mouse and human SMCs, in vivo ADAR1 SMC- and macrophage-specific knockout mouse models combining with molecular, cellular, histological, and pharmacological approaches, we will 1) determine the mechanisms by which ADRA1 promotes MMP2/9 production and activities through its editing and non-editing function; and 2) establish the mechanism by which ADAR1 regulates MΦ activation; and 3) determine if SMC- or myeloid-specific deletion of ADAR1 attenuates AAA formation. Successful completion of the proposed studies will establish novel mechanisms regulating SMC inflammatory phenotype and vascular inflammation, which are likely to advance our understanding of the AAA formation and ultimately lead to novel strategies for developing effective therapeutics to treat AAA.

摘要/摘要腹主动脉瘤（AAA）是一种缺乏主动脉壁药物治疗的潜在致命疾病。炎症和随后的细胞外基质（ECM）蛋白降解，尤其是弹性蛋白断裂，决定血管炎症发生的因素，特别是巨噬细胞。激活和炎症 SMC 表型，导致产生破坏 ECM 的蛋白水解酶体内平衡导致血管壁减弱，从而形成 AAA。然而，有一个关键因素。关于控制血管炎症和血管炎症的机制或关键因素的知识差距 ECM 失调。我们令人兴奋的初步数据表明腺苷脱氨酶作用于 RNA 1 (ADAR1)。在诱导炎症 SMC 表型、巨噬细胞激活和 AAA 形成中发挥核心作用。小鼠中 ADAR1 缺陷 (ADAR1+/-) 显着减弱 AAA 形成（弹性蛋白断裂减少 ADAR1 敲低或敲除也会抑制炎症 SMC 经测试，ADAR1 敲除可抑制表型和巨噬细胞激活。炎症表型标志物，包括 SMC 中的基质金属蛋白酶 2 和 9 (MMP2/9)，同时恢复此外，当ADAR1被删除时，经典的MΦ激活被阻断。 ADAR1 表达与人类患者的动脉瘤形成相关。这些数据有力地支持了这一观点。 ADAR1 诱导炎症 SMC 表型和巨噬细胞活化的新假设，导致血管炎症、弹性蛋白断裂以及随后的 AAA 形成（使用原代小鼠和人类）。 SMC、体内 ADAR1 SMC 和巨噬细胞特异性敲除小鼠模型结合分子、细胞、组织学和药理学方法，我们将 1) 确定 ADRA1 的机制通过其编辑和非编辑功能促进 MMP2/9 的生产和活动；2) 建立 ADAR1 调节 MΦ 激活的机制；3) 确定 SMC 或骨髓特异性删除 ADAR1 减弱 AAA 的形成。成功完成拟议的研究将建立新的研究成果。调节 SMC 炎症表型和血管炎症的机制，这可能会促进我们的研究了解 AAA 的形成并最终导致开发有效疗法的新策略治疗 AAA。