The Role of RAGE in Diabetes and Myocardial Infarction.

RAGE 在糖尿病和心肌梗塞中的作用。

• 批准号: 8329110
• 负责人: Karen O'Shea
• 金额: $ 5.22万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2014-09-25
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8329110
• 关键词: Acute; Address; Adult; Advanced Glycosylation End Products; Affect; Anterior Descending Coronary Artery; Apoptosis; Apoptotic; Biological Preservation; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular system; Cell Death; Cell Death Signaling Process; Chronic; Collaborations; Coronary artery; Cytoplasmic Tail; Data; Development; Diabetes Mellitus; Diabetic mouse; Down-Regulation; Echocardiography; Endothelial Cells; Event; Failure; Family; Future; Generations; Genetic Variation; Goals; Heart; Heart failure; Homeostasis; Hour; Hypoxia; Infarction; Injury; Investigation; Ischemia; Knowledge; Laboratories; Lead; Left; Left Ventricular Dysfunction; Ligands; Ligation; Mediating; Mediator of activation protein; Metabolic; Mitochondria; Mitochondrial Proteins; Modeling; Modification; Molecular Biology Techniques; Morbidity - disease rate; Mouse Strains; Mus; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardium; Necrosis; Oxidative Stress; Pathway interactions; Phosphorylation; Predisposition; Property; Reactive Oxygen Species; Recovery; Recovery of Function; Regulation; Reperfusion Injury; Reperfusion Therapy; Research; Research Personnel; Role; Signal Pathway; Signal Transduction; Stress; Techniques; Testing; Tissues; Training; Transducers; Transgenic Mice; Translating; Up-Regulation; Ventricular Remodeling; Wild Type Mouse; career; cell motility; cell type; diabetic; diabetic patient; experience; genetic strain; improved; in vivo; insight; macrophage; meetings; member; mitochondrial dysfunction; mitochondrial permeability transition pore; monocyte; mortality; non-diabetic; novel; nutrition; outcome forecast; post-doctoral training; prevent; receptor; receptor for advanced glycation endproducts; response; rho GTP-Binding Proteins; skills; therapeutic target

DESCRIPTION (provided by applicant): Myocardial infarction is a major contributor to morbidity and mortality and is exacerbated by diabetes. However, the mechanisms underlying this increased susceptibility to cardiac injury in diabetic patients are not well understood. Previous studies by our laboratory have revealed a central role for the receptor for advanced glycation end-products (RAGE) in myocardial infarction, as global deletion of RAGE resulted in decreased myocardial necrosis, increased functional recovery and preservation of ATP compared to wild-type littermates 48 hours after ischemia/reperfusion (I/R). RAGE is expressed in multiple cell types that impact the myocardial response to I/R injury, such as monocytes/macrophages, endothelial cells, and cardiomyocytes. We have uncovered that RAGE contributes to oxidative stress consequent to I/R and influences mitochondrial dysfunction that accompanies injury to the heart. Ligands for RAGE are increased under diabetic conditions and after I/R, leading to increased downstream signaling. Our laboratory has discovered that the RAGE cytoplasmic domain interacts with diaphanous-1 (mDia-1), a member of the formin family, and an effector of Rho GTPases. The overall goal of the proposed research is to investigate RAGE/mDia1 signaling in cardiomyocytes in response to I/R injury. We predict that cardiomyocyte-specific RAGE and mDia, both highly upregulated in the murine heart after I/R, signal devastating metabolic consequences in the myocardium, which trigger mitochondrial dysfunction. Ideally, this research will translate into an improved prognosis for diabetic patients who have undergone myocardial infarction. To meet this goal, we will use the left anterior descending coronary artery ligation model of I/R in strains of diabetic and non- diabetic mice with genetic variations in RAGE and mDia1 expression. We will assess differences in I/R-induced left ventricular dysfunction due to genetic strain by echocardiography. Additionally, we will perform more targeted studies of hypoxia/reoxygenation in cardiomyocytes isolated from wild type and transgenic mice. We will use the ex vivo perfused heart model to assess mitochondrial function. My proposed studies will provide information to guide future efforts for the treatment of diabetic patients who have undergone myocardial infarction and prevent the development of further complications. In addition, this project will help me accomplish my training goals, which are to 1) characterize and use transgenic mice to test the hypothesis that RAGE/mDia1 signaling lead to devastating metabolic consequences in the myocardium, 2) use primary cardiomyocytes to address the mechanisms involved, 3) employ the ex vivo perfused heart model of ischemia/reperfusion to address the hypothesis, and 4) master the use of physiologically relevant models to assess I/R injury. The successful completion of this research will increase my knowledge, skill set, and potential to achieve my ultimate goal of becoming an independent researcher in cardiovascular disease.

描述（由申请人提供）：心肌梗塞是发病率和死亡率的主要原因，并且因糖尿病而加剧。然而，糖尿病患者心脏损伤易感性增加的机制尚不清楚。我们实验室之前的研究揭示了晚期糖基化终末产物（RAGE）受体在心肌梗死中的核心作用，因为与野生型同窝仔鼠相比，缺血/再灌注（I/R）后48小时，RAGE的整体缺失导致心肌坏死减少、功能恢复增加和ATP保存。 RAGE 在多种细胞类型中表达，这些细胞类型影响心肌对 I/R 损伤的反应，例如单核细胞/巨噬细胞、内皮细胞和心肌细胞。我们发现，RAGE 会导致 I/R 引起的氧化应激，并影响伴随心脏损伤的线粒体功能障碍。 RAGE 配体在糖尿病条件下和 I/R 后增加，导致下游信号传导增加。我们的实验室发现 RAGE 胞质结构域与 diaphanous-1 (mDia-1) 相互作用，diaphanous-1 (mDia-1) 是福尔明 (formin) 家族的成员，也是 Rho GTPases 的效应子。本研究的总体目标是研究心肌细胞中 RAGE/mDia1 信号传导对 I/R 损伤的反应。我们预测，缺血再灌注后小鼠心脏中心肌细胞特异性的 RAGE 和 mDia 均高度上调，预示着心肌中破坏性的代谢后果，从而引发线粒体功能障碍。理想情况下，这项研究将改善患有心肌梗塞的糖尿病患者的预后。为了实现这一目标，我们将在具有 RAGE 和 mDia1 表达遗传变异的糖尿病和非糖尿病小鼠品系中使用左冠状动脉前降支结扎 I/R 模型。我们将通过超声心动图评估遗传应变引起的 I/R 引起的左心室功能障碍的差异。此外，我们将对从野生型和转基因小鼠中分离的心肌细胞的缺氧/复氧进行更有针对性的研究。我们将使用离体灌注心脏模型来评估线粒体功能。我提出的研究将为指导未来治疗患有心肌梗塞的糖尿病患者并防止进一步并发症的发展提供信息。此外，该项目将帮助我实现我的培训目标，即 1) 表征并使用转基因小鼠来测试 RAGE/mDia1 信号传导导致心肌破坏性代谢后果的假设，2) 使用原代心肌细胞来解决所涉及的机制，3) 采用缺血/再灌注的离体灌注心脏模型来解决该假设，4) 掌握 评估 I/R 损伤的生理相关模型。这项研究的成功完成将增加我的知识、技能和潜力，以实现成为心血管疾病独立研究员的最终目标。