Human Angiotensin II Receptor Gene Regulation

描述（由申请人提供）：疾病如动脉粥样硬化、糖尿病、高脂血症和高血压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。虽然许多因素影响这些细胞的变化，血管紧张素II（Ang II）似乎是最重要的一个。在病理条件下，通过其血管收缩、促有丝分裂、促炎症和促纤维化作用，Ang II有助于改变血管张力、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（现在称为AT 1 R）介导的。我们推测AT 1 R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，AT 1 R的表达水平主要是由转录后机制调节。目前的提案代表了第一次深入研究，以调查转录后机制，调节人类AT 1 R基因。本研究的具体目的是：（1）研究hAT 1 R mRNA 3 '-UTR多聚腺苷酸化位点选择的分子调控机制;（2）验证3'-UTR调控hAT 1 R mRNA稳定性的假说;（3）验证3 '-UTR调控hAT 1 R mRNA翻译效率的假说;（4）检验hAT 1 R表达可通过microRNA与hAT 1 R mRNAs的3 '-UTR结合来调节的假设;（5）检验hAT 1 R 3 '-UTR多态性（A1166 C）降低miRNA-155和/或miRNA-365抑制hAT 1 R表达的能力的假设。我们假设这些过程的失调可能导致hATIR的过度产生，并可能引发一系列病理事件，最终导致心血管疾病。从所提出的研究中获得的知识可能导致开发用于其中发生hAT 1 R表达的异常调节的疾病状态的新疗法。

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.