Kinases-mediated SUMOylation in Diabetic Cardiomyopathy

糖尿病心肌病中激酶介导的 SUMO 化

基本信息

批准号：
7754866
负责人：
Jun-Ichi Abe
金额：
$ 48.82万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-01-15 至 2011-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7754866
关键词：
ATP2A2 Adenovirus Vector Adenoviruses Adrenergic Receptor Adult Affect Angiotensin II Animals Apoptosis Binding Biochemical Budgets Canada Cardiac Cardiac Myocytes Cicatrix Clinical Clinical Research Congenital Heart Defects Coronary Arteriosclerosis Cyclic AMP Cyclic AMP-Responsive DNA-Binding Protein Data Deceleration Diabetes Mellitus Diagnosis Dominant-Negative Mutation Doppler Echocardiography Down-Regulation Evaluation Event FVB Mouse Feedback Figs - dietary Frequencies Functional disorder Genetic Transcription Glucose Goals Gold Grant Heart Heart Diseases Heart Rate Heart failure Hydrogen Peroxide Hyperglycemia Image In Vitro Induction of Apoptosis Inhibition of Apoptosis Intervention Kinetics Left Left Ventricular Dysfunction Left Ventricular Function Left Ventricular Remodeling Letters Ligase Limb structure MAPK7 gene Measurement Measures Mediating Methods Mitogen-Activated Protein Kinases Mitral Valve Modeling Modification Molecular Morbidity - disease rate Mus Muscle Cells Myocardial Myocardial Infarction Ontario Outcome PDE3A gene product Pattern Perioperative Phosphorylation Phosphotransferases Physiologic intraventricular pressure Play Principal Investigator Protocols documentation Publishing Reactive Oxygen Species Reagent Relaxation Renin-Angiotensin System Reperfusion Injury Reporting Research Personnel Resolution Risk Factors Role Signal Transduction Small Interfering RNA Streptozocin System Systolic Pressure Time Transcription Repressor/Corepressor Transcriptional Regulation Transduction Gene Transgenic Mice Ubiquitin Ventricular Ventricular Function Viral Vector Work aortic valve base diabetic diabetic cardiomyopathy diabetic patient hemodynamics in vivo inhibitor/antagonist injured mortality non-diabetic novel novel therapeutics operation pressure programs protein inhibitor of activated STAT 1 receptor expression research study small molecule time interval

项目摘要

DESCRIPTION (provided by applicant): Perioperative myocardial infarction (MI) remains a significant clinical problem and diabetes is an independent risk factor for both mortality and morbidity after MI. A number of clinical studies have shown that the post-MI left ventricular function is significantly worse in diabetic compared with non- diabetic patients. However, what is lacking is a plausible relationship between diabetes and any of the known regulators of myocyte apoptosis known to play a significant role in the post-MI cardiac dysfunction. Recently, we have demonstrated that a novel signaling between phosphodiesterase 3A (PDE3A) and inducible cAMP early repressor (ICER), the PDE3A-ICER feedback loop, is a likely mechanism determining the fate of injured myocytes. Our recent preliminary data to be presented in this proposal indicate that ERK5, an atypical mitogen activated protein kinase with transcriptional activity, regulates the PDE3A-ICER feedback loop and that the ERK5 transcriptional activity itself is subjected to down regulation by a hyperglycemia- dependent small ubiquitin-related modification (SUMO). p90RSK, a kinase activated in diabetes, increases ERK5-SUMOylation and inhibits its transcriptional activity. Our working hypothesis is that inhibition of ERK5 transcriptional activity in diabetic heart by p90RSK-mediated ERK5-SUMOylation results in a proapoptotic condition likely to contribute to poor post-MI cardiac ventricular function. The specific aims are: Aim 1: Determine the role of p90RSK activation on streptozotocin-induced exacerbation of left ventricular remodeling after MI, in vivo. Aim 2. Determine the role of p90RSK-ERK5 axis on streptozotocin- induced exacerbation of LV remodeling after MI in vivo. Aim 3: Determine the molecular mechanisms by which p90RSK functions as an inhibitor for ERK5 transcriptional activity in cardiomyocytes, in vitro. Aim 4: Determine the role of angiotensin II, reactive oxygen species and high glucose-mediated endogenous p90RSK activation and subsequent ERK5-SUMOylation in PDE3A-ICER feedback loop-mediated apoptosis and inhibition of SERCA2 and 21-adrenergic receptor expression in vitro, and we will investigate the functional significance of the molecular interaction between p90RSK and ERK5 transcriptional regulation through extensive use of adenovirus in an in vitro myocyte ststem. The broad-based experimental approach including the use of various transgenic mice and gene transduction viral vectors should allow us to determine the importance of p90RSK-ERK5 axis in diabetic cardiomyopathy. Moreover, we believe that our novel small molecule specific p90RSK inhibitor should provide a new therapeutic strategy for reducing post- ischemic cardiac dysfunction in diabetics.

描述（由申请人提供）：围手术期心肌梗死（MI）仍然是一个重要的临床问题，糖尿病是 MI 后死亡率和发病率的独立危险因素。大量临床研究表明，与非糖尿病患者相比，糖尿病患者心肌梗死后左心室功能明显较差。然而，糖尿病与任何已知的心肌细胞凋亡调节因子之间缺乏合理的关系，已知这些调节因子在心肌梗死后心功能障碍中发挥重要作用。最近，我们证明磷酸二酯酶 3A (PDE3A) 和诱导型 cAMP 早期阻遏蛋白 (ICER) 之间的新信号传导（PDE3A-ICER 反馈环路）可能是决定受损心肌细胞命运的机制。我们在本提案中提出的最新初步数据表明，ERK5（一种具有转录活性的非典型丝裂原激活蛋白激酶）调节 PDE3A-ICER 反馈环，并且 ERK5 转录活性本身受到高血糖依赖性小泛素的下调相关修改（SUMO）。 p90RSK 是一种在糖尿病中激活的激酶，可增加 ERK5-SUMO 化并抑制其转录活性。我们的工作假设是，p90RSK 介导的 ERK5-SUMO 化对糖尿病心脏中 ERK5 转录活性的抑制导致促凋亡状态，可能导致 MI 后心室功能不良。具体目标是：目标 1：体内确定 p90RSK 激活对链脲佐菌素诱导的 MI 后左心室重构恶化的作用。目标 2. 确定 p90RSK-ERK5 轴在体内 MI 后链脲佐菌素诱导的 LV 重塑加剧中的作用。目标 3：在体外确定 p90RSK 作为心肌细胞 ERK5 转录活性抑制剂的分子机制。目标 4：确定血管紧张素 II、活性氧和高葡萄糖介导的内源性 p90RSK 激活以及随后的 ERK5-SUMO 化在 PDE3A-ICER 反馈环介导的细胞凋亡以及体外 SERCA2 和 21-肾上腺素能受体表达抑制中的作用，我们将通过在体外肌细胞干细胞中广泛使用腺病毒来研究 p90RSK 和 ERK5 转录调控之间分子相互作用的功能意义。包括使用各种转基因小鼠和基因转导病毒载体在内的广泛实验方法应该使我们能够确定 p90RSK-ERK5 轴在糖尿病心肌病中的重要性。此外，我们相信我们的新型小分子特异性 p90RSK 抑制剂应该为减少糖尿病患者缺血后心功能障碍提供新的治疗策略。