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ADAR1 in abdominal aortic aneurysm

ADAR1 在腹主动脉瘤中的作用

基本信息

批准号：
10330543
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/10330543
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 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 therapeutically effective 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/文摘