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

• 批准号: 8399013
• 负责人: RAMA NATARAJAN
• 金额: $ 39.51万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8399013
• 关键词: Acetylation; Adopted; Angiotensin II; Animal Model; Aorta; Atherosclerosis; Biochemical; Bioinformatics; Biological Assay; Biology; Blood Vessels; Candidate Disease Gene; Cardiovascular Diseases; Cardiovascular system; Cell Culture Techniques; Cells; Chromatin; Chromatin Structure; Clinical; DNA Methylation; Data; Diabetes Mellitus; Diabetic mouse; Disease; Docking; Drug Targeting; Environment; Enzymes; Epigenetic Process; Event; Extracellular Matrix; Functional RNA; Functional disorder; Gene Expression; Gene Expression Regulation; Gene Silencing; Genes; Goals; Growth; Healthcare; Healthcare Systems; Histone H3; Histones; Human; Hypertension; Hypertrophy; Inflammatory; Knowledge; Lead; Link; Lysine; Malignant Neoplasms; Mediating; Messenger RNA; Methylation; MicroRNAs; Molecular Profiling; Morbidity - disease rate; National Heart, Lung, and Blood Institute; Nuclear; Obese Mice; Pathologic; Pathology; Patients; Play; Population; Post-Translational Protein Processing; Property; Publishing; Reactive Oxygen Species; Receptor, Angiotensin, Type 1; Regulation; Resources; Role; Signal Pathway; Signal Transduction; Site; Small RNA; Smooth Muscle Myocytes; Strategic Planning; Technology; Testing; Therapeutic; Transcriptional Regulation; Transferase; Translations; Untranslated Regions; Variant; Work; base; cardiovascular disorder therapy; chromatin immunoprecipitation; chromatin remodeling; deep sequencing; diabetic; epigenome; genome sequencing; genome-wide; histone modification; improved; in vivo; in vivo Model; inhibitor/antagonist; innovation; insight; mRNA Expression; mRNA Transcript Degradation; migration; monocyte; mortality; mouse model; new therapeutic target; next generation; next generation sequencing; novel; peptide hormone; promoter; receptor; response; therapeutic target; transcription factor; transcriptome sequencing; vascular smooth muscle cell proliferation

Project Summary Atherosclerotic and hypertensive cardiovascular diseases (CVDs) are major causes of morbidity and mortality and a severe strain on our healthcare system. The peptide hormone Angiotensin II (Ang II) plays a major role in these pathologies due to its vasoconstrictive, pro-oxidant, -growth and -inflammatory properties in target cells such as vascular smooth muscle cells (VSMC). Several studies have documented the biochemical and signaling mechanisms of Ang II actions via the type 1 receptor (AT1R) in VSMC. However, the precise nuclear epigenetic mechanisms involved in AngII induced transcriptional regulation of pathological genes are not clear. It is increasingly recognized that profound alterations in chromatin structure, including changes in epigenetic posttranslational modifications (PTMs) of histones, such as Histone H3 -lysine methylation (H3Kme) can regulate the "active" or "inactive" state of genes. Recent evidence has also demonstrated the key roles of microRNAs (miRs) in gene regulation by posttranscriptional mechanisms. Our goal is to evaluate such epigenetic and miR mechanisms in Ang II actions in order to unravel new therapeutic targets. We hypothesize that the dysregulation of histone H3Kme and aberrant expression of key miRs contribute to Ang II induced VSMC dysfunction associated with various CVDs. This will be tested via 3 Specific Aims using state-of-the-art genome-wide profiling and bioinformatics approaches in cell culture along with relevant mouse models. Specific Aim 1 is to perform epigenome profiling of key chromatin histone H3Kme marks in VSMC treated with and without Ang II, evaluate the chromatin enzymes regulating these marks, and then their functional roles in VSMC. Specific Aim 2 is to profile the miR signatures in VSMC in response to Ang II and then determine the functional relevance of key differentially expressed miRs. Specific Aim 3 is to evaluate specific mouse models of increased Ang II action in order to determine the in vivo relevance of the epigenetic marks and miRs uncovered in Aims 1 and 2. When completed, the proposed work will yield novel new data describing the epigenetic and miR profiles of VSMC under Ang II treated conditions, and also bring in new next generation genome sequencing technologies to the field of vascular biology. The results can increase our understanding of Ang II actions, and identify new targets that might be developed as clinical therapies for CVDs such as hypertension and atherosclerosis.

项目摘要 动脉粥样硬化和高血压心血管疾病（CVD）是发病率的主要原因 和死亡率以及对我们的医疗保健系统的严重压力。肽激素血管紧张素II （ANG II）由于其血管收缩，氧化，生长，在这些病理学中起主要作用 靶细胞（例如血管平滑肌细胞（VSMC））中的 - 炎症特性。 几项研究记录了ANG II作用的生化和信号传导机制 通过VSMC中的1型受体（AT1R）。但是，精确的核表观遗传机制 参与ANGII诱导的病理基因转录调控尚不清楚。这是 越来越认识到染色质结构的深刻改变，包括改变 组蛋白的表观遗传后翻译后修饰（PTMS），例如组蛋白H3-赖氨酸 甲基化（H3kMe）可以调节基因的“活性”或“非活性”状态。最近的证据有 还证明了microRNA（miR）在转录后基因调控中的关键作用 机制。我们的目标是评估ANG II动作中的这种表观遗传和miR机制 为了解开新的治疗靶标。我们假设组蛋白的失调 H3kMe和关键miR的异常表达有助于ANG II引起的VSMC功能障碍 与各种CVD相关。这将通过3个特定目的使用最先进的目标进行测试 全基因组的分析和生物信息学在细胞培养中以及相关小鼠的方法 型号。特定目的1是执行关键染色质组蛋白H3kMe的表观基因组分析 在有或没有ANG II处理的VSMC中的标记，评估调节的染色质酶 这些标记，然后在VSMC中的功能角色。特定目标2是介绍mir VSMC中的签名响应ANG II，然后确定密钥的功能相关性 差异表达的mir。特定目标3是评估增加的特定鼠标模型 ANG II动作以确定表观遗传标记和miR的体内相关性 在目标1和2中发现。完成后，拟议的工作将产生新的新数据 描述ANG II处理条件下VSMC的表观遗传和miR谱，也描述 将新的下一代基因组测序技术带入血管生物学领域。 结果可以增加我们对Ang II行动的理解，并确定可能 作为CVD（例如高血压和动脉粥样硬化）的临床疗法发展。