A Role for Mena in the Heart

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的表达是心衰的一个新的预测因子。此外，在小鼠HF基因修复后，Mena表达正常化，在人类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。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。正常心脏Mena表达从新生儿逐渐降低到成人低水平。我们的初步数据表明，Mena-/-小鼠出现进行性心功能障碍，纤维化，传导异常，心脏损伤的病理反应加剧。我们假设增加的Mena表达在HF中具有保护作用，可能是对心脏应激的重要代偿反应，最终被其他因素所取代。Mena功能的调节通过camp依赖性蛋白激酶A （PKA）的磷酸化发生。在急性2-AR刺激下，Mena被camp依赖性蛋白激酶A （PKA）磷酸化，显示出增加的膜定位和与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。总的来说，我们的数据表明Mena在心脏中起着重要作用。为了验证Mena的表达、活性以及与Ezrin的相互作用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，我们提出了以下三个具体目的。每个目标都利用基因工程小鼠模型，体外研究，分离心肌细胞收缩性和体内表征。1. 确定Mena在心脏基线和对病理性心脏刺激的反应中的作用。2. 确定Mena磷酸化在调节心功能和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：本提案涉及关于Mena在心脏中的作用及其与2-ARs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。本研究旨在确定新发现的名为Mena的hf相关基因的功能作用，可能提供新的诊断/治疗靶点。

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Mena expression is protective in HF and may be an important compensatory response to cardiac stress ultimately superceded by other factors.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.