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：
10022134
负责人：
Jeff Zheying Chen
金额：
$ 5.05万
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 2022-11-01
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10022134
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.

抽象的胸主动脉瘤（TAAs）是一种常见的、临床上无症状的主动脉扩张。然而，这种疾病的并发症——例如主动脉夹层和破裂——是突然且致命的。因为有目前尚无有效的药物疗法可以预防或逆转主动脉扩张，所有胸主动脉扩张患者动脉瘤最终需要手术修复。马凡综合征是由原纤维蛋白-1 突变引起的，原纤维蛋白-1 是一种大型细胞外基质蛋白，负责弹性蛋白结构和主动脉完整性。我们的项目建议使用马凡氏综合症模型小鼠研究 TAA 的发病机制。我们已经证明 TAA 发生在血管紧张素受体（AT1a 受体）依赖性方式。 AT1a受体如何在马凡综合征中被激活是目前的一个空白知识。 AT1a 受体通常由其主要效应肽血管紧张素 II 激活。也可以是以不依赖于配体的方式激活。我们假设马凡综合征中的 AT1a 受体是以 AngII 依赖性方式激活。此外，我们假设内源性 AngII 的耗竭通过抑制 AT1a 受体活性，充分减弱马凡综合征中 TAA 的发展。为了检验这一假设，我们将确定血管紧张素原反义是否会耗尽 AngII 寡核苷酸给药可减弱主动脉扩张、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 AngII 形成的抑制、血管紧张素受体阻断或 β-阻断是否与对马凡综合征患者的 TAA 具有保护作用。总而言之，该项目的完成将有助于更好地理解分子机制马凡氏综合征的背后关联着胸主动脉瘤的发病机制。