Human Angiotensin II Receptor Gene Regulation

人血管紧张素 II 受体基因调控

基本信息

批准号：
7257880
负责人：
TERRY S ELTON
金额：
$ 25.49万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1992
资助国家：
美国
起止时间：
1992-08-01 至 2010-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7257880
关键词：
5&apos Untranslated Regions Affinity Alternative Splicing Angiotensin II Angiotensin II Receptor Angiotensin II Type 1 Receptor Blockers Angiotensin-Converting Enzyme Inhibitors Apoptosis Atherosclerosis Binding Biological Blood Vessels Cardiovascular Diseases Cell physiology Clinical Research Condition Depth Development Diabetes Mellitus Disease Etiology Event Exclusion Exons Fibrosis Functional disorder Funding G-Protein-Coupled Receptors Gene Expression Gene Expression Regulation Genes Genetic Polymorphism Heart Hypertrophy Heart failure Hormones Human Hyperlipidemia Hypertension Inflammation Inflammatory Investigation Knowledge Laboratories Lead Mediating Messenger RNA MicroRNAs Molecular Numbers Open Reading Frames Play Polyadenylation Process Proteins RNA Splicing Receptor Gene Regulation Relative (related person)Research Project Grants Reverse Transcriptase Polymerase Chain Reaction Role Site Testing Transcript Untranslated Regions Variant Vascular remodeling Vasoconstrictor Agents cell growth glomerulosclerosis human tissue mRNA Stability migration novel therapeutics response vascular inflammation vpr Genes

项目摘要

DESCRIPTION (provided by applicant): Diseases such as atherosclerosis, diabetes, hyperlipidemia and hypertension are associated with vascular function and structural changes including endothelial dysfunction, altered contractility and vascular remodeling. Although many factors influence these cellular changes, angiotensin II (Ang II) appears to be one of the most important. In pathological conditions, through its vasoconstrictor, mitogenic, proinflammatory and profibrotic actions, Ang II contributes to altered vascular tone, endothelial dysfunction, structural remodeling and vascular inflammation. Many of the known functions of Ang II are mediated via a high affinity G protein-coupled receptor, now designated AT1R. We hypothesize that aberrant regulation of AT1R levels may play a pivotal role in cardiovascular disease. A number of recent studies suggest that AT1R expression levels are predominantly regulated by post-transcriptional mechanisms. The current proposal represents the first in-depth study to investigate the post-transcriptional mechanisms that regulate the human AT1R gene. The Specific Aims of the Proposal are to: (1) Investigate the molecular mechanisms that regulate the selection of hAT1R mRNA 3'-UTR polyadenylation sites; (2) Test the hypothesis that the 3'- UTR regulates hAT1R mRNA stability; (3) Test the hypothesis that the 3'-UTR regulates the translational efficiency of hAT1R mRNAs; (4) Test the hypothesis that hAT1 R expression can be regulated by the binding of microRNAs to the 3'-UTR of hAT1R mRNAs; (5) Test the hypothesis that the hAT1R 3'-UTR polymorphism (A1166C) reduces the ability of miRNA-155 and/or miRNA-365 to inhibit hAT1R expression. We hypothesize that dysregulation of these processes may lead to the overproduction of hATIRs and may initiate a cascade of pathological events and eventually lead to cardiovascular disease. The knowledge gained from the proposed study may lead to the development of novel therapeutics for disease states in which aberrant regulation of hAT1 R expression occurs.

描述（由申请人提供）：动脉粥样硬化、糖尿病、高脂血症和高血压等疾病与血管功能和结构变化相关，包括内皮功能障碍、收缩性改变和血管重塑。尽管影响这些细胞变化的因素有很多，但血管紧张素 II (Ang II) 似乎是最重要的因素之一。在病理条件下，Ang II 通过其血管收缩、促有丝分裂、促炎和促纤维化作用，导致血管张力改变、内皮功能障碍、结构重塑和血管炎症。 Ang II 的许多已知功能都是通过高亲和力 G 蛋白偶联受体（现在称为 AT1R）介导的。我们假设 AT1R 水平的异常调节可能在心血管疾病中发挥关键作用。最近的许多研究表明 AT1R 表达水平主要受转录后机制调节。目前的提案代表了第一个深入研究调节人类 AT1R 基因的转录后机制。该提案的具体目标是：（1）研究调节hAT1R mRNA 3'-UTR多腺苷酸化位点选择的分子机制； (2)检验3'-UTR调节hAT1R mRNA稳定性的假设； (3)检验3'-UTR调节hAT1R mRNA翻译效率的假设； (4)检验hAT1R表达可以通过microRNA与hAT1R mRNA的3'-UTR结合来调节的假设； (5)检验hAT1R 3'-UTR多态性(A1166C)降低miRNA-155和/或miRNA-365抑制hAT1R表达的能力的假设。我们假设这些过程的失调可能导致 hATIR 的过量产生，并可能引发一系列病理事件，最终导致心血管疾病。从拟议的研究中获得的知识可能会导致针对 hAT1 R 表达异常调节的疾病状态的新疗法的开发。