Regulation of AT1R-signaling and pathology in vessels through microRNA

通过 microRNA 调节血管中 AT1R 信号传导和病理学

基本信息

批准号：
8485661
负责人：
Sadashiva S Karnik
金额：
$ 37.37万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-01 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8485661
关键词：
Accounting Angiotensin II Angiotensin II Receptor Angiotensin II Type 1 Receptor Blockers Angiotensin Receptor Angiotensinogen Angiotensins Antihypertensive Agents Aorta Aortic Aneurysm Atherosclerosis Binding Biochemical Biogenesis Biology Blood Pressure Blood Vessels Brain Cardiac Cardiac Myocytes Cardiovascular Diseases Cardiovascular Physiology Cardiovascular system Cell Line Cell Survival Cell model Cells Cholesterol Chronic Chronic Disease Chymosin Data Dilated Cardiomyopathy Disease Disease Progression Down-Regulation Drug Targeting Epithelial Cells Experimental Models Fibrosis Functional RNA Functional disorder Gene Expression Gene Expression Regulation Gene Targeting Genetic Transcription Goals Health Heart Heart Hypertrophy Heart failure Homeostasis Hormones Human Hypertrophy Infusion procedures Intervention Kidney Knock-in Mouse Knowledge Link Mammary Neoplasms Mediating Mediator of activation protein Messenger RNA MicroRNAs Mitogen-Activated Protein Kinases Modeling Molecular Molecular Analysis Molecular Profiling Mus Muscle Cells Organ Pathology Pathway interactions Pattern Peptidyl-Dipeptidase A Physiological Prevention Process Protein Tyrosine Kinase Proteins Public Health Receptor Activation Receptor Cell Receptor Signaling Receptor, Angiotensin, Type 1 Regulation Regulator Genes Renin-Angiotensin System Research Role Signal Transduction Smooth Muscle Myocytes Staging Stimulus Study models System Testing Therapeutic Tissues Transcript Transgenic Mice Tumor Angiogenesis Type 2 Angiotensin II Receptor Up-Regulation Water-Electrolyte Balance base cell growth gain of function heart cell hemodynamics improved in vivo kidney cell kidney vascular structure knowledge base mutant novel nucleotide analog programs receptor receptor coupling response tumor growth

项目摘要

DESCRIPTION (provided by applicant): The long-term goal of our research program is to elucidate microRNA mechanisms that alter normal regulation of genes in response to overactivity of the angiotensin II type 1 receptor (AT1R). Angiotensin II (AngII) is the classical mediator of the effects of the renin-angiotensin system on the cardiovascular homeostasis. This receptor regulates gene expression targeted by the AT1R-blockers (ARB), a widely used class of anti- hypertensive drugs that are currently in trial for the prevention of vascular, renal and cardiac hypertrophy, aortic aneurism, vascular fibrosis, breast tumor growth and angiogenesis. Inhibition of AT1R in renal, vascular and cardiac cells by ARBs is protective, but the activation o the receptor causes hypertrophy and progressive fibrosis of the respective organs/tissues. In preliminary studies we have discovered that chronic activation of AT1R deregulates gene expression through both transcriptional and post-transcriptional mechanisms. To directly link deregulation of gene expression to hypertrophy and fibrosis, we profiled mRNA and microRNA (miRNA) expression in the AT1R TG mice aorta, heart, and in HL1-AT1R (cardiomyocyte) and the VSMC-AT1R cell lines. Typical transcriptional and miRNA regulatory mechanisms are significantly altered in all of the experimental models. In a separate study, we have shown significantly altered miRNA expression profile in dilated cardiomyopathy human hearts. The altered miRNAs target gene networks that do account for compensatory remodeling in human heart failure. These novel studies suggest that mRNA and miRNA profiles, together, contribute to AT1R biology in health and disease. Our current proposal will focus on the novel roles of two AT1R-modulated microRNAs: miR-205 and mir-483. Three Specific Aims are proposed to test the hypothesis that specific transcriptional and post-transcriptional regulatory mechanisms tilt the dynamics of typical hypertrophy and fibrosis signaling towards a disease connotation. They are: (i) to determine miR-205 mechanisms which alter critical signaling components in models of hypertrophy and fibrosis, (ii) to determine the miR-483 mechanism of up-regulation of the rennin angiotensin system, and (iii) to determine the AT1R regulated mechanisms of biogenesis and the stability of miR-205 and miR-483. If the AT1R activity is not regulated properly, AngII stimulus becomes chronic and can damage the tissue, as well as contribute to chronic disorders of blood vessels, kidney and heart. A clear understanding of these mechanisms is important to improve the therapeutic application of ARBs. These proposed studies will advance our knowledge of the biology of AT1R signaling causing hypertrophy and fibrosis. There is potential relevance for this knowledge base in understanding normal functioning aorta, vasculature in brain, kidney and heart, as well as the pathology of heart failure, atherosclerosis and aortic aneurysm.

描述（由申请人提供）：我们研究计划的长期目标是阐明 microRNA 机制，这些机制会改变基因的正常调节，以响应血管紧张素 II 1 型受体 (AT1R) 的过度活跃。血管紧张素 II (AngII) 是肾素-血管紧张素系统对心血管稳态影响的经典介质。该受体调节 AT1R 阻滞剂 (ARB) 靶向的基因表达，AT1R 阻滞剂是一类广泛使用的抗高血压药物，目前正在试验用于预防血管、肾脏和心脏肥大、主动脉瘤、血管纤维化、乳腺肿瘤生长和血管生成。 ARB 对肾、血管和心肌细胞中 AT1R 的抑制具有保护作用，但受体的激活会导致相应器官/组织肥大和进行性纤维化。在初步研究中，我们发现 AT1R 的慢性激活通过转录和转录后机制解除基因表达的调节。为了直接将基因表达失调与肥大和纤维化联系起来，我们分析了 AT1R TG 小鼠主动脉、心脏、HL1-AT1R（心肌细胞）和 VSMC-AT1R 细胞系中 mRNA 和 microRNA (miRNA) 的表达。典型的转录和 miRNA 调控机制在所有实验模型中都发生了显着改变。在另一项研究中，我们发现扩张型心肌病人类心脏中 miRNA 表达谱显着改变。改变的 miRNA 靶标基因网络确实解释了人类心力衰竭的代偿性重塑。这些新颖的研究表明，mRNA 和 miRNA 谱共同对健康和疾病中的 AT1R 生物学做出了贡献。我们目前的提案将重点关注两种 AT1R 调节的 microRNA 的新作用：miR-205 和 mir-483。提出了三个具体目标来检验特定转录和转录后调节机制使典型肥大和纤维化信号传导向疾病内涵倾斜的假设。它们是：（i）确定改变肥大和纤维化模型中关键信号传导成分的 miR-205 机制，（ii）确定肾素血管紧张素系统上调的 miR-483 机制，以及（iii）确定AT1R 调节 miR-205 和 miR-483 的生物发生机制和稳定性。如果 AT1R 活性未得到适当调节，AngII 刺激就会变成慢性，并可能损害组织，并导致血管、肾脏和心脏的慢性疾病。清楚地了解这些机制对于改善 ARB 的治疗应用非常重要。这些拟议的研究将增进我们对 AT1R 信号传导导致肥大和纤维化的生物学知识。该知识库对于了解正常功能的主动脉、脑、肾和心脏的脉管系统以及心力衰竭、动脉粥样硬化和主动脉瘤的病理学具有潜在的相关性。