Human Angiotensin II Receptor Gene Regulation

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改变有关，包括内皮功能障碍、收缩性改变和血管重塑。尽管许多因素影响这些细胞变化，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，通过其血管收缩、有丝分裂、促炎和促纤维化作用，Ang II有助于血管张力改变、内皮功能障碍、结构重塑和血管炎症。Ang II的许多已知功能是通过高亲和力G蛋白偶联受体介导的，现在称为AT1R。我们假设AT1R水平的异常调节可能在心血管疾病中起关键作用。最近的一些研究表明，AT1R的表达水平主要受转录后机制的调节。目前的建议是第一次深入研究调节人类AT1R基因的转录后机制。该提案的具体目的是：(1)研究调节hAT1R mRNA 3'-UTR聚腺苷化位点选择的分子机制；(2)验证3'- UTR调控hAT1R mRNA稳定性的假设；(3)验证3'-UTR调控hAT1R mrna翻译效率的假设；(4)验证microrna结合hAT1R mrna的3′-UTR调控hAT1R表达的假设；(5)验证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hat1r表达异常调节的疾病状态的新疗法的发展。

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.