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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：
8657108
负责人：
Sadashiva S Karnik
金额：
$ 38.47万
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/8657108
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(申请人提供)：我们研究计划的长期目标是阐明在血管紧张素II 1型受体(AT1R)过度活动时改变基因正常调节的microRNA机制。血管紧张素II(AngII)是肾素-血管紧张素系统影响心血管内稳态的经典介质。该受体调节AT1R受体阻滞剂(ARB)靶向的基因表达，ARB是一类广泛使用的抗高血压药物，目前正在试验中，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AT1R的抑制是保护性的，但受体的激活会导致相应器官/组织的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来解除对基因表达的调控。为了直接将基因表达的失控与肥大和纤维化联系起来，我们对AT1R TG小鼠的主动脉、心脏以及HL1-AT1R(心肌细胞)和VSMC-AT1R细胞系中的mRNA和microRNA(MiRNA)的表达进行了分析。在所有的实验模型中，典型的转录和miRNA调节机制都发生了显著的变化。在另一项单独的研究中，我们发现扩张型心肌病患者的miRNA表达谱发生了显著变化。改变的miRNAs针对的是基因网络，这些基因网络确实解释了人类心力衰竭的代偿性重构。这些新的研究表明，mRNA和miRNA图谱共同有助于AT1R在健康和疾病中的生物学。我们目前的建议将集中在两个AT1R调节的microRNAs：miR-205和mir-483的新角色上。提出了三个具体的目标来检验这一假说，即特定的转录和转录后调控机制使典型的肥大和纤维化信号的动力学向疾病内涵倾斜。它们是：(I)确定改变肥大和纤维化模型中关键信号成分的miR-205机制，(Ii)确定上调肾素血管紧张素系统的miR-483机制，以及(Iii)确定AT1R调节生物发生的机制以及miR-205和miR-483的稳定性。如果AT1R活性调节不当，血管紧张素转换酶刺激就会变成慢性刺激，并可能损害组织，并导致血管、肾脏和心脏的慢性疾病。对这些机制的清楚理解对于提高ARBS的治疗应用具有重要意义。这些拟议的研究将促进我们对AT1R信号导致肥大和纤维化的生物学知识的了解。这一知识库在了解正常功能的主动脉、脑、肾和心脏的血管系统以及心力衰竭、动脉粥样硬化和主动脉瘤的病理方面具有潜在的相关性。