Mechanisms of renin angiotensin modulation in thoracic aortic aneurysms

胸主动脉瘤肾素血管紧张素调节机制

基本信息

批准号：
10242785
负责人：
Jeff Zheying Chen
金额：
$ 4.35万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2022-05-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10242785
关键词：
3-Dimensional Angiotensin II Angiotensin Receptor Angiotensin Type 1a Receptor Angiotensin-Converting Enzyme Inhibitors Angiotensinogen Angiotensins Antisense Oligonucleotides Aorta Aortic Rupture Attenuated Binding Bioinformatics Breeding Cardiomyopathies Clinical Clinical Research Collagen Communication Research Confocal Microscopy Data Data Set Databases Deposition Development Dilatation - action Dilated Cardiomyopathy Dimensions Disease Dissection Elastin Electron Microscopy Electronic Health Record Enzyme Inhibition Enzymes Extracellular Matrix Extracellular Matrix Proteins FBN1 Genetic Goals Growth Half-Life Health Hemorrhage Human Knowledge Ligands Losartan MADH2 gene MAPK3 gene Marfan Syndrome Matrix Metalloproteinases Measurement Measures Mechanics Medial Medical Modeling Molecular Mus Mutation Nitric Oxide Operative Surgical Procedures Pathogenesis Patients Peptides Peptidyl-Dipeptidase A Pharmaceutical Preparations Pharmacology Phosphorylation Plant Roots Process Production Publishing RNA Interference Receptor Activation Renin Reporting Research Ethics Risk Rupture Signal Transduction Specificity Stretching Structure Sudden Death Testing Thoracic Aortic Aneurysm Training Transforming Growth Factor beta Ultrasonography Vascular Smooth Muscle Visualization base extracellular inhibitor/antagonist mortality mouse model prevent protective effect receptor repaired transdifferentiation

项目摘要

ABSTRACT Thoracic aortic aneurysms (TAAs) are a common, clinically-silent dilatation of the aorta. However, complications of this disease - such as aortic dissection and rupture - are sudden and deadly. Because there is currently no validated medical therapy to prevent or reverse aortic dilation, all patients with thoracic aortic aneurysms will eventually need surgical repair. Marfan syndrome is caused by mutations in fibrillin-1, a large extracellular matrix protein responsible for elastin structure and aortic integrity. Our project proposes the use of Marfan syndrome model mice to investigate the pathogenesis of TAAs. We have shown that TAAs occur in an angiotensin receptor (AT1a receptor) dependent manner. How AT1a receptors are activated in Marfan syndrome is a gap in current knowledge. AT1a receptors are canonically activated by its main effector peptide, angiotensin II. It can also be activated in a ligand independent manner. We hypothesize that AT1a receptors in Marfan syndrome are activated in an AngII dependent manner. Furthermore, we hypothesize that depletion of endogenous AngII sufficiently attenuates TAA development in Marfan syndrome through inhibition of AT1a receptor activity. To test this hypothesis, we will determine if AngII depletion by angiotensinogen antisense oligonucleotide administration attenuates aortic dilation, aortic medial remodeling, and aortic AT1a receptor activity. We will also perform a retrospective clinical study using a large electronic health record dataset to determine if inhibition of AngII formation, angiotensin receptor blockade, or beta-blockade are associated with protection against TAA in Marfan syndrome patients. Altogether, completion of this project will provide a better understanding of the molecular mechanism behind Marfan syndrome associated thoracic aortic aneurysm pathogenesis.

抽象的胸动脉瘤（TAAS）是主动脉的常见，临床上的扩张。然而，这种疾病的并发症（例如主动脉夹层和破裂）是突然而致命的。因为有目前尚未经过验证的医疗疗法以预防或逆转主动脉膨胀，所有胸腔主动脉症患者 aneurysms will eventually need surgical repair. Marfan syndrome is caused by mutations in fibrillin-1, a large extracellular matrix protein responsible for elastin structure and aortic integrity. Our project proposes the use of Marfan syndrome model mice to 研究TAA的发病机理。我们已经表明TAA发生在血管紧张素受体中（AT1A 受体）依赖方式。在Marfan综合征中如何激活AT1A受体是电流的差距知识。 AT1A受体通过其主要效应肽血管紧张素II在典型上激活。也可以以配体独立的方式激活。我们假设Marfan综合征的AT1A受体是以Angii依赖性方式激活。此外，我们假设内源性ANGII的耗竭 sufficiently attenuates TAA development in Marfan syndrome through inhibition of AT1a receptor activity. To test this hypothesis, we will determine if AngII depletion by angiotensinogen antisense 寡核苷酸给药可减弱主动脉膨胀，主动脉内侧重塑和主动脉AT1A受体活动。我们还将使用大型电子健康记录数据集进行回顾性临床研究确定抑制Angii形成，血管紧张素受体阻断或β受体阻滞是否与在Marfan综合征患者中保护TAA。总之，该项目的完成将更好地理解分子机制马凡氏综合症背后相关的胸动脉瘤发病机理。