A Role for Mena in the Heart

梅纳在心中的角色

• 批准号: 7844227
• 负责人: Burns C Blaxall
• 金额: $ 23.8万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/7844227
• 关键词: A kinase anchoring protein; ADRBK1 gene; Ablation; Actins; Acute; Address; Adrenergic Agents; Adrenergic Receptor; Adult; Animals; Axon; Beta-Adrenergic Receptor Kinase 1; Biology; Cardiac; Cardiac Myocytes; Cardiovascular system; Cells; Chronic; Coupling; Cultured Cells; Cyclic AMP-Dependent Protein Kinases; Cytoskeletal Proteins; Data; Disease; Dominant-Negative Mutation; Dose; Down-Regulation; Drosophila genus; Echocardiography; Electrocardiogram; Failure; Fibrosis; Functional disorder; Gene Expression; Gene Expression Profiling; Genes; Genetic; Genetically Engineered Mouse; Goals; Heart; Heart failure; Histopathology; Homologous Gene; Human; Hybrids; In Vitro; Injury; Investigation; Laboratories; Left; Mediating; Membrane; Microfilaments; Modeling; Molecular Biology; Molecular Profiling; Morphology; Mus; Names; Natriuretic Factors; Nature; Pathologic; Pathway interactions; Pattern; Peptides; Phenotype; Phosphorylation; Phosphotransferases; Physiological; Play; Proteins; Recycling; Regulation; Reperfusion Injury; Reporting; Research Personnel; Role; STK6 gene; Signal Transduction; Signaling Protein; Stimulus; Stress; System; Techniques; Testing; Time; Tissues; Transgenic Model; Transgenic Organisms; Up-Regulation; adrenergic; base; career; desensitization; ezrin; fetal; hemodynamics; in vivo; loss of function; malignant breast neoplasm; member; migration; mimetics; model development; morphometry; mouse model; mutant; neonate; novel; novel diagnostics; outcome forecast; overexpression; programs; protein protein interaction; response; response to injury; therapeutic target; tool; trafficking; ventricular assist device

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有关。我们最近发现MENA的表达是一种新的心力衰竭预测因子。此外，在对小鼠的心衰进行遗传挽救以及在人类获得有益的左心室辅助装置支持后，MENA的表达恢复正常。MENA可改变微丝动力学，并与与心衰有关的细胞骨架蛋白相互作用。它的适当表达和定位是正常轴突迁移所必需的，它的表达与乳腺癌有关。正常心肌肌膜蛋白的表达在成人中从新生儿到低水平逐渐减少。我们的初步数据表明，Mena-/-小鼠发展为进行性心功能障碍、纤维化、传导异常，并加剧了对心脏损伤的病理反应。我们推测，增加的MENA表达对心衰有保护作用，可能是对心脏应激的一种重要的代偿反应，最终被其他因素取代。通过cAMP依赖的蛋白激酶A(PKA)的磷酸化来调节膜蛋白的功能。作为对急性2-AR刺激的响应，MENA被cAMP依赖的蛋白激酶A(PKA)磷酸化，显示出增加的膜定位以及与Ezrin、肌动蛋白和其他已知调节2-AR信号和细胞骨架动力学的蛋白质的相互作用。总体而言，我们的数据表明Mena在心脏中扮演着重要的角色。为了验证这一假设，即在基础和病理生理条件下，调节MENA的表达、活性及其与Ezrin的相互作用在心脏和2-AR功能中发挥重要作用，我们提出了以下三个具体目标。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能力和体内表征。1.确定MENA在心脏基础状态和对病理性心脏刺激的反应中的作用。2.确定MENA磷酸化在心功能和2-AR信号转导中的作用。3.确定Mena-Ezrin相互作用在心肌细胞功能和2-AR信号转导中的性质和作用。研究结果：这项建议涉及到关于MENA心脏作用的基础心血管生物学，以及它与2-AR的潜在相互作用和调节。心力衰竭是一种预后不佳的衰弱疾病。这项建议旨在确定新发现的名为Mena的心力衰竭相关基因的功能作用，可能提供新的诊断/治疗靶点。