Interrogating the Role and Regulation of EGR2 in the Diabetic Heart

探究 EGR2 在糖尿病心脏中的作用和调节

基本信息

批准号：
10065793
负责人：
Luke A Potter
金额：
$ 3.65万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-10 至 2023-09-09
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10065793
关键词：
Address Adult Affect Binding Biological Assay Biopsy CRISPR/Cas technology Cardiac Cardiac Myocytes Cardiovascular Diseases Categories Cell Death ChIP-seq Clinical Complement Congestive Heart Failure Coronary Arteriosclerosis DNA DNA Methylation DNA sequencing DNMT3a Data Development Diabetes Mellitus Diabetic mouse Diagnosis Diagnostic Diuretics EGR2 gene Echocardiography Epigenetic Process Etiology Fibrosis Functional disorder Future Gene Expression Gene Expression Regulation Genes Genetic Transcription Global Change Glucose Glucose Transporter Growth Guide RNA Heart Heart Hypertrophy Heart failure Human Hyperglycemia Hyperlipidemia Hypertension Hypertrophy Immunoblotting Impairment In Vitro Insulin deficiency Knock-out Laboratories Left ventricular structure Lentivirus Vector Literature Luciferases Measures Mediating Messenger RNA Methylation Modification Molecular Molecular Biology Morbidity - disease rate Mus Myocardial Ischemia Myocardial dysfunction Nerve Neurons Nodal Operative Surgical Procedures Paper Pathology Pathway interactions Patients Pattern Play Population Process Proteins Regulation Regulator Genes Reporter Reporting Research Resistance Risk Risk Factors Role Sampling Signal Transduction Site Streptozocin Structure of beta Cell of islet System Systemic Scleroderma Testing Time Tissues Toxic effect Training Transcript Transcriptional Activation Transgenic Model Treatment Efficacy Trichrome stain Weight Work base bisulfite bisulfite sequencing cardiometabolism coronary fibrosis demethylation diabetic diabetic cardiomyopathy diabetic patient experimental study falls glycemic control heart function human data in vivo mortality mouse model myelination nerve injury non-diabetic novel novel therapeutics overexpression patient population pressure promoter response skills targeted treatment transcription factor transcriptome sequencing transcriptomics vector

项目摘要

Project Summary Diabetes mellitus, independent of coronary artery disease, hypertension, or other risk factors, is associated with up to a 4-fold increase in risk of developing heart failure (HF). While other etiologies of heart failure have effective therapeutics such as diuretics and inotropes, diabetic HF is often resistant or unresponsive to these. Thus, the development of targeted therapies to address the underlying cardiac pathology unique to diabetic HF is essential. Clinical evidence suggests that diabetic hyperglycemia imparts long term elevated risks for heart failure, even after correction. Dr. Wende’s laboratory tests the hypothesis that this aberrant glucose flux, as seen in diabetes mellitus, contributes to the development of cardio-metabolic dysfunction via epigenetic changes. Recent work in his laboratory has detected a distinct signature of promoter-associated DNA demethylation in human diabetic HF that corresponds with inversely altered transcriptional activity. Specifically, using both RNA-sequencing and Illumina Methy450K array studies on cardiac biopsies taken during surgery, we found the transcription factor early growth response 2 (EGR2) had significant decreases in promoter methylation and a concurrent increase in transcript levels unique to HF samples from diabetic patients. Similarly, both RNA-sequencing and bisulfite treated DNA sequencing of cardiac tissue from diabetic mice revealed the same pattern of hypomethylation and increased expression of Egr2. Relatively little is known about the transcription factor EGR2 in the heart, as significant previous work has focused on its regulation of neuronal myelination in the context of nerve development and response to nerve injury. However, recent reports have highlighted a possible role for EGR2 in regulating cardiac hypertrophy in response to pressure overload, and other papers have shown that EGR2 plays a pro-fibrotic role in systemic sclerosis. Therefore, we hypothesize that EGR2 is a nodal transcription factor which mediates diabetes-associated cardiac dysfunction, fibrosis, and hypertrophy in response to demethylation of its promoter. This proposal will test the following three aims: (1) Determine whether EGR2 expression is sufficient to induce cardiac dysfunction, fibrosis, and hypertrophy noted in diabetic mice, (2) determine whether EGR2 expression is necessary for the cardiac dysfunction, fibrosis, and hypertrophy noted in diabetic mice, and (3) determine whether transcriptional activation of Egr2 is dependent on promoter DNA methylation. In summary, determining whether EGR2 is a novel transcription regulator of cardiac function may define a novel mechanism through which the heart could be epigenetically reprogramed to reverse the toxic effects of hyperglycemia in diabetic heart failure.

项目摘要糖尿病，独立于冠状动脉疾病，高血压或其他危险因素，与心力衰竭（HF）的风险高达4倍。而心力衰竭的其他病因有效糖尿病性HF等治疗剂（例如利尿剂和肌力）通常对这些糖尿病性或无反应性。那，开发针对糖尿病HF独特的潜在心脏病理的靶向疗法至关重要。临床证据表明，糖尿病性高血糖赋予了长期升高心力衰竭的风险，即使校正后。 Wende博士的实验室测试了以下假设：这种异常的葡萄糖通量，如糖尿病所见 Mellitus，通过表观遗传学变化有助于心脏代谢功能障碍的发展。最近的工作他的实验室发现了人类糖尿病中与启动子相关的DNA脱甲基化的独特签名 HF与转录活性相反的相对应。具体而言，使用RNA-setering和 Illumina Methy450k阵列研究在手术期间进行的心脏活检，我们发现了转录因子早期增长反应2（EGR2）的启动子甲基化和同时增加的下降在糖尿病患者的HF样品中独有的转录水平。同样，RNA - 测序和硫酸含量糖尿病小鼠的心脏组织的DNA测序显示出相同的低甲基化模式和 EGR2的表达增加。关于心脏中的转录因子Egr2的了解相对鲜为人知，因为在神经的背景下，先前的重要工作集中于其神经元髓鞘的调节对神经损伤的发展和反应。但是，最近的报告强调了EGR2的可能作用在控制压力超负荷的心脏肥大时，其他论文表明EGR2 在系统性硬化症中起促纤维化作用。因此，我们假设Egr2是淋巴结转录因子介导与糖尿病相关的心脏功能障碍，纤维化和肥大响应脱甲基化其发起人。该建议将测试以下三个目的：（1）确定egr2表达是否为足以诱导糖尿病小鼠中注意到的心脏功能障碍，纤维化和肥大，（2）确定是否是否确定 EGR2表达对于糖尿病小鼠中注意到的心脏功能障碍，纤维化和肥大是必需的，并且（3）确定EGR2的转录激活是否取决于启动子DNA甲基化。总之，确定EGR2是否是心脏功能的新型转录调节剂可能会定义一种新型机制可以通过表观遗传进行重新编程，以扭转高血糖在糖尿病心力衰竭。