A Role for Mena in the Heart

梅纳在心中的角色

基本信息

批准号：
8217284
负责人：
Burns C Blaxall
金额：
$ 24.71万
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：
2008-04-14 至 2013-01-01
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8217284
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 Fibrosis Functional disorder Gene Expression Gene Expression Profile 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 Peptides Phenotype Phosphorylation Phosphotransferases Physiological Play Proteins Receptor Signaling 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

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有关。我们最近发现MENA的表达是HF的新型预测指标。此外，在小鼠中HF的基因营救后，MENA表达归一化，并在人类中有益左心室辅助装置支持。 MENA可以改变微丝动力学，并与与HF有关的细胞骨架蛋白相互作用。正常的轴突迁移需要其适当的表达和定位，并且其表达与乳腺癌有关。成年人的正常心脏MENA表达从新生儿逐渐降低到低水平。我们的初步数据表明MENA - / - 小鼠会发展为心脏功能障碍，纤维化，传导异常以及对心脏损伤的病理反应加剧。我们假设增加的MENA表达在HF中具有保护性，并且可能是对心脏应激的重要补偿性反应，最终由其他因素取代。 MENA功能的调节是通过CAMP依赖性蛋白激酶A（PKA）通过磷酸化而发生的。为了响应急性2AR刺激，MENA被CAMP依赖性蛋白激酶A（PKA）磷酸化，显示出膜的定位增加以及与Ezrin，肌动蛋白和其他已知调节2-AR信号传导和细胞骨骼动力学的已知蛋白质的相互作用。总体而言，我们的数据表明，欧洲局在心脏中起着重要的作用。为了检验以下假设：在基础和病理生理条件下，在心脏和2AR功能中，MENA表达，活性和与Ezrin的相互作用在心脏和2AR功能中起重要作用，我们提出以下三个特定目标。每个目标都利用基因工程的小鼠模型，体外研究，孤立的心肌细胞收缩力和体内表征。 1。确定MENA在基线和病理心脏刺激的响应时的心脏中的作用。 2。确定MENA磷酸化在调节心脏功能和2AR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2AR信号传导中的性质和作用。相关性：该提案涉及有关MENA的心脏作用及其与2-ARS的潜在相互作用和调节的基本心血管生物学。心脏失败是一种令人衰弱的疾病，预后不良。该提案旨在确定新近鉴定的HF相关基因的功能作用，称为MENA，可能提供新颖的诊断/治疗靶标。