GADD45B and Metabolic Memory in Diabetic Heart Failure

项目摘要 拟议研究项目的总体目标是确定糖尿病是否表观遗传 导致心脏衰竭糖尿病导致心力衰竭的风险增加4倍 (HF)与冠状动脉疾病或高血压无关。HF的其他病因通过药物管理 具有相对疗效;然而，糖尿病HF对这些一线药物具有耐药性。Glycoprotein控制 建议降低HF风险;然而，这仍然存在争议，并且没有有效的治疗方案， 糖尿病患者一旦出现HF症状。因此，逆转糖尿病相关的靶向治疗， 心脏的变化可以改变疾病的进程，并改善生活质量和寿命。 为了了解糖尿病心脏中HF的潜在发病机制，我们研究了以下领域： 表观遗传学，其特征是环境刺激的整合，作为稳定的调节影响， 基因表达。具体来说，我们感兴趣的是确定在多大程度上， 代谢环境由表观遗传变化引起或促成。之前的研究已经发现了 DNA甲基化的改变--一种与转录抑制相关的常见表观遗传标记-- 和缺血性心力衰竭中的转录谱。然而，控制心脏的调节影响 DNA甲基化仍然知之甚少，DNA甲基化对心脏的影响也是如此。 糖尿病我们的初步数据揭示了启动子相关DNA的功能独特的签名 糖尿病HF患者左心室的去甲基化。使用组合的“组学”方法，我有 随后确定生长停滞和DNA损伤诱导45-β（GADD45 B）可能是中枢神经系统疾病。 在糖尿病人类和小鼠心脏衰竭中强烈诱导的调节因子。 关于心脏中的GADD 45 B知之甚少，因为以前的工作主要集中在其对心脏的调节上。 记忆形成过程中的神经元活性DNA去甲基化。在其他组织中，GADD 45 B已经被 显示协调细胞生长和凋亡，以响应氧化应激，如那些产生的 通过脂肪酸氧化。因此，我们假设GADD 45 B介导了糖尿病相关的心脏损害。 通过脂肪酸敏感性蛋白酶介导的关键凋亡中间体的活性DNA去甲基化导致的功能障碍 机制本研究的主要目的是：（1）验证GADD 45 B基因可能被 治疗靶向恢复糖尿病心脏的心脏功能，和（2）测试假设， 糖尿病环境通过自身调节DNA去甲基化增强心肌细胞GADD 45 B诱导。 完成这一建议也将提供一个基础，我的职业生涯作为一个医生，科学家与工具箱 创新技术和基本技能。

PROJECT SUMMARY The overall objective of the proposed research project is to determine whether diabetes mellitus epigenetically programs the heart to fail. Diabetes mellitus confers up to a 4-fold increased risk of developing heart failure (HF) independently of coronary artery disease or hypertension. Other etiologies of HF are medically managed with relative efficacy; however, diabetic HF is resistant to these first-line agents. Glycemic control has been proposed to reduce HF risk; however, this remains controversial, and no effective treatment regimen exists for diabetic patients once symptoms of HF develop. Thus, a targeted therapy that reverses diabetes-associated cardiac changes could alter the disease course and improve both quality and duration of life. In order to understand the underlying pathogenesis of HF in a diabetic heart, we have looked to the field of epigenetics, which characterizes the integration of environmental stimuli as stable regulatory influences on gene expression. Specifically, we are interested in determining the extent to which disturbances in the metabolic milieu are caused by or contribute to epigenetic changes. Previous work has identified a connection between alterations in DNA methylation - a common epigenetic mark associated with repressed transcription - and the transcriptional profile in ischemic heart failure. However, the regulatory influences governing cardiac DNA methylation remain poorly understood, as does the impact of DNA methylation on the heart in the context of diabetes mellitus. Our preliminary data reveal a functionally-distinct signature of promoter-associated DNA demethylation in the left ventricle of patients with diabetic HF. Using a combined ‘-omics’ approach, I have subsequently identified Growth Arrest and DNA Damage Inducible 45-beta (GADD45B) as a likely central regulator that is robustly induced in the failing diabetic human and mouse heart. Relatively little is known about GADD45B in the heart, as previous work has focused largely on its regulation of neuronal active DNA demethylation in the context of memory formation. In other tissues, GADD45B has been shown to orchestrate cellular growth and apoptosis in response to oxidative stress, such as those generated via fatty acid oxidation. Accordingly, we hypothesize that GADD45B mediates diabetes-associated cardiac dysfunction via active DNA demethylation of key apoptotic intermediates through a fatty acid-sensitive mechanism. This proposal will test the following two aims: (1) Test the hypothesis that GADD45B can be therapeutically targeted to restore cardiac function in the diabetic heart, and (2) Test the hypothesis that the diabetic milieu potentiates cardiomyocyte GADD45B induction via auto-regulatory DNA demethylation. Completion of this proposal will also provide a foundation for my career as a physician-scientist with a toolbox of both innovative techniques and essential skills.