A Role for Mena in the Heart
梅纳在心中的角色
基本信息
- 批准号:7844227
- 负责人:
- 金额:$ 23.8万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-07-15 至 2011-06-30
- 项目状态:已结题
- 来源:
- 关键词:A kinase anchoring proteinADRBK1 geneAblationActinsAcuteAddressAdrenergic AgentsAdrenergic ReceptorAdultAnimalsAxonBeta-Adrenergic Receptor Kinase 1BiologyCardiacCardiac MyocytesCardiovascular systemCellsChronicCouplingCultured CellsCyclic AMP-Dependent Protein KinasesCytoskeletal ProteinsDataDiseaseDominant-Negative MutationDoseDown-RegulationDrosophila genusEchocardiographyElectrocardiogramFailureFibrosisFunctional disorderGene ExpressionGene Expression ProfilingGenesGeneticGenetically Engineered MouseGoalsHeartHeart failureHistopathologyHomologous GeneHumanHybridsIn VitroInjuryInvestigationLaboratoriesLeftMediatingMembraneMicrofilamentsModelingMolecular BiologyMolecular ProfilingMorphologyMusNamesNatriuretic FactorsNaturePathologicPathway interactionsPatternPeptidesPhenotypePhosphorylationPhosphotransferasesPhysiologicalPlayProteinsRecyclingRegulationReperfusion InjuryReportingResearch PersonnelRoleSTK6 geneSignal TransductionSignaling ProteinStimulusStressSystemTechniquesTestingTimeTissuesTransgenic ModelTransgenic OrganismsUp-Regulationadrenergicbasecareerdesensitizationezrinfetalhemodynamicsin vivoloss of functionmalignant breast neoplasmmembermigrationmimeticsmodel developmentmorphometrymouse modelmutantneonatenovelnovel diagnosticsoutcome forecastoverexpressionprogramsprotein protein interactionresponseresponse to injurytherapeutic targettooltraffickingventricular assist device
项目摘要
DESCRIPTION (provided by applicant): Heart failure (HF) is associated with myriad changes in cardiac gene expression. We recently found expression of Mena to be a novel predictor of HF. Furthermore, Mena expression is normalized following a genetic rescue of HF in mice, and following beneficial left ventricular assist device support in humans. Mena can alter microfilament dynamics and interacts with cytoskeletal proteins implicated in HF. Its appropriate expression and localization are required for normal axon migration, and its expression has been associated with breast cancer. Normal cardiac Mena expression is progressively decreased from neonate to low levels in the adult. Our preliminary data indicate Mena-/- mice develop progressive cardiac dysfunction, fibrosis, conduction abnormality, and exacerbated pathologic response to cardiac injury. We hypothesize increased Mena expression is protective in HF and may be an important compensatory response to cardiac stress ultimately superceded by other factors. Regulation of Mena function occurs via phosphorylation by cAMP-dependent protein kinase A (PKA). In response to acute 2-AR stimulation, Mena is phosphorylated by cAMP-dependent protein kinase A (PKA), shows increased membrane localization and interaction with Ezrin, actin and other proteins known to regulate both 2-AR signaling and cytoskeletal dynamics. Collectively, our data suggest Mena plays an important role in the heart. To test the hypothesis that regulation of Mena expression, activity and interaction with Ezrin plays an important role in cardiac and 2-AR function under basal and pathophysiologic conditions, we propose the following three specific aims. Each aim utilizes genetically engineered mouse models, in vitro studies, isolated cardiomyocyte contractility, and in vivo characterization. 1. Determine the role of Mena in the heart at baseline and in response to pathologic cardiac stimuli. 2. Determine the role of Mena phosphorylation in modulating cardiac function and 2-AR signaling. 3. Determine the nature and role of Mena-Ezrin interactions in cardiomyocyte function and 2-AR signaling. RELEVENCE: This proposal addresses fundamental cardiovascular biology regarding the cardiac role of Mena and its potential interactions with and regulation by 2-ARs.Heart failure is a debilitating disease with poor prognosis. This proposal aims to determine the functional role of the newly identified HF-associated gene named Mena, potentially providing novel diagnostic/therapeutic targets.
描述(由申请人提供):心力衰竭(HF)与心脏基因表达的无数变化相关。我们最近发现 Mena 的表达是心力衰竭的新预测因子。此外,在小鼠中对心力衰竭进行基因拯救后,以及在人类中进行有益的左心室辅助装置支持后,Mena 表达正常化。 Mena 可以改变微丝动力学并与 HF 相关的细胞骨架蛋白相互作用。其适当的表达和定位是正常轴突迁移所必需的,并且其表达与乳腺癌相关。正常心脏的 Mena 表达从新生儿到成人的低水平逐渐降低。我们的初步数据表明 Mena-/- 小鼠出现进行性心脏功能障碍、纤维化、传导异常以及对心脏损伤的病理反应加剧。我们假设 Mena 表达增加在心力衰竭中具有保护作用,并且可能是对最终被其他因素取代的心脏应激的重要代偿反应。 Mena 功能的调节是通过 cAMP 依赖性蛋白激酶 A (PKA) 的磷酸化来实现的。响应急性 2-AR 刺激,Mena 被 cAMP 依赖性蛋白激酶 A (PKA) 磷酸化,显示膜定位增加以及与 Ezrin、肌动蛋白和其他已知调节 2-AR 信号传导和细胞骨架动力学的蛋白质的相互作用增加。总的来说,我们的数据表明梅纳在心脏中发挥着重要作用。为了检验 Mena 表达、活性以及与 Ezrin 相互作用的调节在基础和病理生理条件下心脏和 2-AR 功能中发挥重要作用的假设,我们提出以下三个具体目标。每个目标都利用基因工程小鼠模型、体外研究、分离的心肌细胞收缩性和体内表征。 1. 确定 Mena 在基线时和对病理性心脏刺激的反应中在心脏中的作用。 2. 确定 Mena 磷酸化在调节心脏功能和 2-AR 信号传导中的作用。 3. 确定 Mena-Ezrin 相互作用在心肌细胞功能和 2-AR 信号传导中的性质和作用。相关性:该提案涉及关于 Mena 的心脏作用及其与 2-AR 的潜在相互作用和调节的基础心血管生物学。心力衰竭是一种预后不良的衰弱性疾病。该提案旨在确定新发现的心力衰竭相关基因 Mena 的功能作用,可能提供新的诊断/治疗靶点。
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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Burns C Blaxall其他文献
Burns C Blaxall的其他文献
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- 批准号:
7890141 - 财政年份:2010
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8056631 - 财政年份:2010
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