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:7555914
- 负责人:
- 金额:$ 48.51万
- 依托单位:
- 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:
- 关键词:ATP2A2Adenovirus VectorAdenovirusesAdrenergic ReceptorAngiotensin IIAnimal WelfareApoptosisBibliographyBindingBiochemicalCardiacCardiac MyocytesClinicalClinical ResearchCountryCyclic AMPCyclic AMP-Responsive DNA-Binding ProteinDataDiabetes MellitusDominant-Negative MutationDown-RegulationEnvironmentEnvironmental ImpactEquipmentFeedbackFunctional disorderGenetic TranscriptionGlucoseHeartHeart failureHydrogen PeroxideHyperglycemiaIACUCIn VitroInduction of ApoptosisInhibition of ApoptosisInternationalLeft Ventricular FunctionLeft Ventricular RemodelingLigaseMAPK7 geneMediatingMitogen-Activated Protein KinasesModificationMolecularMorbidity - disease rateMusMuscle CellsMyocardial InfarctionPDE3A gene productPerioperativePhosphorylationPhosphotransferasesPlayPrincipal InvestigatorReactive Oxygen SpeciesReagentRenin-Angiotensin SystemReportingResearchResearch Ethics CommitteesResourcesRisk FactorsRoleSignal TransductionStreptozocinSystemTranscription Repressor/CorepressorTranscriptional RegulationTransduction GeneTransgenic MiceUbiquitinVentricular FunctionVertebratesViral VectorWorkYangabstractingbasediabeticdiabetic cardiomyopathydiabetic patientexpirationhuman subjectin vivoinhibitor/antagonistinjuredmortalitynon-diabeticnovelnovel therapeuticsprogramsprotein inhibitor of activated STAT 1receptor expressionsmall molecule
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风险因素。大量临床研究表明,糖尿病患者心肌梗死后左心室功能明显差于非糖尿病患者。然而,缺乏的是糖尿病和任何已知的心肌细胞凋亡调节因子之间的合理关系,这些调节因子已知在MI后心功能障碍中起重要作用。最近,我们已经证明,磷酸二酯酶3A(PDE 3A)和诱导型cAMP早期阻遏物(ICER)之间的一种新的信号传导,PDE 3A-ICER反馈环,是一种可能的机制,决定损伤的心肌细胞的命运。我们最近的初步数据表明,ERK 5,一种具有转录活性的非典型促分裂原活化蛋白激酶,调节PDE 3A-ICER反馈环,并且ERK 5转录活性本身受到高血糖依赖性小泛素相关修饰(SUMO)的下调。p90 RSK是一种在糖尿病中激活的激酶,可增加ERK 5-SUMO化并抑制其转录活性。我们的工作假设是通过p90 RSK介导的ERK 5-SUMO化抑制糖尿病心脏中的ERK 5转录活性,导致可能导致MI后心室功能不良的促凋亡状态。具体目标是:目标1:确定p90 RSK激活在体内MI后链脲佐菌素诱导的左心室重构恶化中的作用。目标2.确定p90 RSK-ERK 5轴在体内MI后链脲佐菌素诱导的LV重构恶化中的作用。目的3:研究p90 RSK在体外心肌细胞中作为ERK 5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p90 RSK激活和随后的ERK 5-SUMO化在PDE 3A-ICER反馈环介导的细胞凋亡和SERCA 2和21-肾上腺素能受体表达的体外抑制中的作用,我们将通过广泛使用腺病毒在体外研究p90 RSK和ERK 5转录调控之间的分子相互作用的功能意义。肌细胞系统广泛的实验方法,包括使用各种转基因小鼠和基因转导病毒载体,使我们能够确定p90 RSK-ERK 5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p90 RSK抑制剂应该为减少糖尿病患者的缺血后心脏功能障碍提供新的治疗策略。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Jun-Ichi Abe其他文献
Jun-Ichi Abe的其他文献
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{{ truncateString('Jun-Ichi Abe', 18)}}的其他基金
Premature aging disorders, metabolites, and atherosclerosis
过早衰老疾病、代谢产物和动脉粥样硬化
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10607893 - 财政年份:2022
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Mitigating radiation-induced cardiovascular disease by inhibiting premature aging
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10425386 - 财政年份:2020
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Mitigating radiation-induced cardiovascular disease by inhibiting premature aging
通过抑制过早衰老减轻辐射诱发的心血管疾病
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10661520 - 财政年份:2020
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Mitigating radiation-induced cardiovascular disease by inhibiting premature aging
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10206042 - 财政年份:2020
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$ 48.51万 - 项目类别:
Pathological flow-induced endothelial damage and plaque erosion
病理性血流诱导的内皮损伤和斑块侵蚀
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9974575 - 财政年份:2019
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$ 48.51万 - 项目类别:
Pathological flow-induced endothelial damage and plaque erosion
病理性血流诱导的内皮损伤和斑块侵蚀
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10201742 - 财政年份:2019
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Pathological flow-induced endothelial damage and plaque erosion
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10430067 - 财政年份:2019
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Disturbed flow-induced TERF2IP post-translational modifications and atherosclerosis.
血流紊乱诱导的 TERF2IP 翻译后修饰和动脉粥样硬化。
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9207134 - 财政年份:2016
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Disturbed flow-induced TERF2IP post-translational modifications and atherosclerosis.
血流紊乱诱导的 TERF2IP 翻译后修饰和动脉粥样硬化。
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9006224 - 财政年份:2016
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PAR 13-233 cART accelerates vascular aging in HIV infected subjects
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9066206 - 财政年份:2014
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