Transcriptional Regulation by Angiotensin II in Vascular Smooth Muscle Cells

血管紧张素 II 在血管平滑肌细胞中的转录调节

基本信息

批准号：
9262456
负责人：
RAMA NATARAJAN
金额：
$ 43.25万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-01-01 至 2020-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9262456
关键词：
Address Affect Angiotensin II Antibodies Aorta Apolipoprotein E Atherosclerosis Attenuated Biological Assay Blood Vessels CRISPR/Cas technology Cardiovascular Diseases Cell physiology Cells ChIP-seq Chromatin Clinical Code Communities Data Disease Enhancers Environment Epigenetic Process Event Functional disorder Funding Gene Expression Gene Targeting Genes Growth Healthcare Histones Hormones Hypertension Hypertrophy In Vitro Inflammation Inflammatory Knowledge Lead Mediating Molecular Morbidity - disease rate Mus Muscle Cells Oligonucleotides Oxidative Stress Pathologic Pathology Patients Pharmaceutical Preparations Population Proteins RNA Reactive Oxygen Species Regulation Reporter Reporting Resources Role Sampling Signal Transduction Small Interfering RNA Technology Testing Therapeutic Transcriptional Regulation Untranslated RNA Vascular Diseases Vascular Smooth Muscle base cell growth chromatin modification chromatin remodeling diabetic genome editing genome-wide genomic profiles histone modification human disease in vivo in vivo Model inhibitor/antagonist innovation insight locked nucleic acid loss of function migration mortality mouse model novel promoter receptor therapeutic target transcriptome sequencing

项目摘要

Cardiovascular diseases (CVDs) such as atherosclerosis and hypertension are the leading causes of morbidity and mortality in our community. Furthermore these vascular complications are accelerated in the diabetic population. Epigenetic mechanisms have been implicated in several common human diseases, including CVDs, due to the influence of the environment which can affect epigenetic states. Evidence shows that the hormone Angiotensin II (Ang II) is a major player in the pathologies of hypertension and atherosclerosis due to its vasoconstrictive, pro-inflammatory, pro-oxidant, and growth promoting effects in target cells such as vascular smooth muscle cells (VSMC). During the previous funding period, we reported the first functional roles for epigenetic chromatin histone modifications and non-coding RNAs in mediating some of these deleterious actions of Ang II in VSMCs. In addition, our new preliminary data show that Ang II can regulate specific novel long non-coding RNAs (lncRNAs), and enhancers in VSMCs that modulate the expression of target genes associated with VSMC inflammation and dysfunction. Despite these advances, the functions of specific lncRNAs and their subtle interactions with other epigenetic factors like enhancers to modulate Ang II-induced gene expression are still not fully understood. Furthermore, the roles of enhancers, superenhancers and specific lncRNAs in Ang II-mediated VSMC dysfunction and related CVDs are not known. Our central hypothesis is that dynamic control of key lncRNAs and VSMC- specific enhancers/superenhancers, as well as epigenetic cross-talk among these factors, contribute to Ang II-induced VSMC dysfunction associated with CVDs. This will be tested through 3 Specific Aims. In Specific Aim 1, we will examine the molecular mechanisms of regulation and functional roles of two novel lncRNAs that we found to be induced by Ang II in VSMCs. In Specific Aim 2, we will define the roles of Ang II-regulated enhancers and superenhancers in the expression of Ang II-regulated genes involved in VSMC functions. In Specific Aim 3, the in vivo expression and functional roles of the two lncRNAs and candidate enhancers/SEs will be examined in mouse models of Ang II induced vascular dysfunction and atherosclerosis. This study examines several new concepts and uses innovative platforms along with functional in vivo models to gain novel insights into VSMC regulatory networks. The results and can have potentially far reaching clinical and therapeutic implications for CVDs.

动脉粥样硬化和高血压等心血管疾病（CVD）是最主要的疾病我们社区发病和死亡的原因。此外，这些血管并发症在糖尿病人群中加速。表观遗传机制涉及由于环境的影响，包括心血管疾病在内的几种人类常见疾病这可以影响表观遗传状态。有证据表明，血管紧张素 II (Ang II) 激素是一种由于其血管收缩作用，它是高血压和动脉粥样硬化病理学的主要参与者，对血管等靶细胞具有促炎、促氧化和生长促进作用平滑肌细胞（VSMC）。在上一个资助期间，我们报告了第一个表观遗传染色质组蛋白修饰和非编码 RNA 的功能作用介导 Ang II 在 VSMC 中的一些有害行为。此外，我们的新初步数据表明Ang II可以调节特定的新型长非编码RNA（lncRNA）， VSMC 中调节与 VSMC 相关靶基因表达的增强子炎症和功能障碍。尽管取得了这些进展，但特定 lncRNA 和它们与其他表观遗传因子（如增强子）的微妙相互作用，以调节 Ang II 诱导的基因表达仍不完全清楚。此外，增强子的作用， Ang II 介导的 VSMC 功能障碍和相关 CVD 中的超级增强子和特异性 lncRNA 不知道。我们的中心假设是关键 lncRNA 和 VSMC 的动态控制特定的增强子/超级增强子，以及这些因素之间的表观遗传串扰，有助于 Ang II 诱导的与 CVD 相关的 VSMC 功能障碍。这将被测试通过 3 个具体目标。在具体目标 1 中，我们将研究以下分子机制：我们发现 Ang II 诱导的两种新型 lncRNA 的调控和功能作用 VSMC。在具体目标 2 中，我们将定义 Ang II 调节的增强子的作用和参与 VSMC 功能的 Ang II 调节基因表达的超级增强子。在具体目标3，两种lncRNA和候选物的体内表达和功能作用将在 Ang II 诱导的血管功能障碍小鼠模型中检查增强子/SE 动脉粥样硬化。这项研究探讨了几个新概念并使用创新平台通过功能性体内模型获得对 VSMC 调控网络的新见解。结果并且可能对心血管疾病产生深远的临床和治疗影响。