RSK Regulation of NFATc and Cardiac Myocyte Hypertrophy
RSK 对 NFATc 和心肌细胞肥大的调节
基本信息
- 批准号:7622690
- 负责人:
- 金额:$ 5.01万
- 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:2008-04-15 至 2010-10-14
- 项目状态:已结题
- 来源:
- 关键词:A kinase anchoring proteinAddressAffectApoptosisBacteriaBindingBinding SitesBiological AssayCalcineurinCardiacCardiac MyocytesCardiac OutputCell NucleusCell physiologyCellsCollaborationsComplexDNA Binding DomainDockingDominant-Negative MutationEchocardiographyFamilyFamily memberGrowthHaresHeartHeart HypertrophyHeart failureHistopathologyHypertrophyIn VitroIndividualInfarctionIschemiaKnockout MiceLeadLigationLuciferasesMAPK7 geneMapsMeasuresMitogen-Activated Protein KinasesMitoticMonitorMusMuscleMuscle CellsMyocardialMyocardial InfarctionNeonatalNuclear EnvelopePDPK1 genePartner in relationshipPathway interactionsPeptidesPhenotypePhosphorylationProtein Binding DomainProtein IsoformsRPS6KA geneRattusRegulationReperfusion TherapyReporterRibosomal Protein S6 KinaseRisk FactorsRoleRouteScaffolding ProteinSignal TransductionSignal Transduction PathwaySignaling MoleculeSiteStressSyndromeTestingTherapeuticTransgenic MiceTreatment Protocolsattenuationcell typehemodynamicsin vivointerestleft coronary arterymortalitymutantnovelnuclear factors of activated T-cellsresponsescaffoldtherapeutic targettranscription factor
项目摘要
DESCRIPTION (provided by applicant): A key compensatory response in the stressed heart is myocyte hypertrophy. Although cardiac hypertrophy can maintain cardiac output in response to elevated wall stress, sustained cardiac hypertrophy is often accompanied by maladaptive remodeling which can ultimately lead to heart failure. Recent evidence suggests that p90 ribosomal S6 kinase (RSK) might be an important regulator of cardiac myocyte hypertrophy. My proposed studies will further our understanding of the role of RSK3 in cardiac remodeling and help determine whether RSK3 would make an attractive therapeutic target for the attenuation of maladaptive hypertrophic signaling. Specific Aim 1: Characterization of a RSK3 binding site within a cardiac myocyte multimolecular signaling complex. I propose to refine the mapping of the predominant RSK3 binding site in mAKAPp and to test whether RSK3 binds to mAKAPp directly using expression in mammalian heterologous cells and bacteria. Specific Aim 2: Studies determining RSK3-dependent NFATc function in myocytes. A potential mechanism by which RSK3 may transduce hypertrophic signaling is through the phosphorylation of the pro-hypertrophic NFATc (nuclear factor of activated T-cells) transcription factor family. I will test whether RSK3 can phosphorylate and activate NFATc family members in neonatal rat cardiac myocytes under conditions that elicit cardiac myocyte hypertrophy in vitro. The effect of RSK3-dependent phosphorylation on NFATc function will be measured using luciferase reporter assays. In addition, I will use mAKAPp RSK3-binding site mutants to test whether RSK3 association with the mAKAPp signalosome is required for NFATc activity and myocyte hypertrophy. Specific Aim 3: The requirement for RSK3 in cardiac hypertrophy in vivo. In order to test whether RSK3 is required for myocyte hypertrophy, I will characterize the phenotype of cardiac-specific RSK3 knock-out mice that have been previously generated. I will challenge the RSK3 mice by left coronary artery ligation and induction of myocardial infarction. Cardiac hypertrophy will be analyzed at one month post-infarction by echocardiography and hemodynamic analysis and by gross and histopathology. Further, in order to address my hypothesis that RSK3 phosphorylation of NFATc isoforms is important for hypertrophy, NFATc activity will be monitored in vivo by mating the cardiac-specific RSK?'' mice to NFAT-luciferase indicator mice.
Cardiac hypertrophy is a leading risk factor for heart failure, and heart failure is a syndrome of major public heath significance affecting 5.2 million US individuals. A better understanding of the mechanisms controlling myocyte hypertrophy may allow for better therapeutic regimens with decreased mortality.
描述(由申请人提供):应激心脏的关键代偿反应是心肌细胞肥大。尽管心脏肥大可以维持心输出量以应对室壁应力升高,但持续的心脏肥大通常伴随着适应不良的重塑,最终可能导致心力衰竭。最近的证据表明 p90 核糖体 S6 激酶 (RSK) 可能是心肌细胞肥大的重要调节因子。我提出的研究将进一步了解 RSK3 在心脏重塑中的作用,并帮助确定 RSK3 是否会成为减弱适应不良肥厚信号传导的有吸引力的治疗靶点。具体目标 1:心肌细胞多分子信号复合物内 RSK3 结合位点的表征。我建议完善 mAKAPp 中主要 RSK3 结合位点的定位,并使用哺乳动物异源细胞和细菌中的表达来测试 RSK3 是否直接与 mAKAPp 结合。具体目标 2:研究确定肌细胞中 RSK3 依赖性 NFATc 功能。 RSK3 转导肥大信号传导的一个潜在机制是通过促肥大 NFATc(激活 T 细胞的核因子)转录因子家族的磷酸化。我将测试在体外引发心肌细胞肥大的条件下,RSK3 是否可以磷酸化并激活新生大鼠心肌细胞中的 NFATc 家族成员。 RSK3 依赖性磷酸化对 NFATc 功能的影响将使用荧光素酶报告基因测定进行测量。此外,我将使用 mAKAPp RSK3 结合位点突变体来测试 RSK3 与 mAKAPp 信号体的关联是否是 NFATc 活性和肌细胞肥大所必需的。具体目标 3:体内心脏肥大对 RSK3 的需求。为了测试肌细胞肥大是否需要 RSK3,我将表征之前生成的心脏特异性 RSK3 敲除小鼠的表型。我将通过结扎左冠状动脉并诱导心肌梗塞来挑战RSK3小鼠。将在梗塞后一个月通过超声心动图和血流动力学分析以及肉眼和组织病理学来分析心脏肥大。此外,为了解决我的假设,即 NFATc 同种型的 RSK3 磷酸化对于肥大很重要,将通过将心脏特异性 RSK?'' 小鼠与 NFAT-荧光素酶指示小鼠交配来体内监测 NFATc 活性。
心脏肥大是心力衰竭的主要危险因素,心力衰竭是一种具有重大公共健康意义的综合征,影响着 520 万美国人。更好地了解控制心肌细胞肥大的机制可能有助于制定更好的治疗方案并降低死亡率。
项目成果
期刊论文数量(0)
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Alejandra Negro其他文献
Alejandra Negro的其他文献
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{{ truncateString('Alejandra Negro', 18)}}的其他基金
RSK Regulation of NFATc and Cardiac Myocyte Hypertrophy
RSK 对 NFATc 和心肌细胞肥大的调节
- 批准号:
7798165 - 财政年份:2008
- 资助金额:
$ 5.01万 - 项目类别:
RSK Regulation of NFATc and Cardiac Myocyte Hypertrophy
RSK 对 NFATc 和心肌细胞肥大的调节
- 批准号:
7485884 - 财政年份:2008
- 资助金额:
$ 5.01万 - 项目类别:
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