Role of Neuregulin/erbB Signaling in the Adult Heart

描述(申请人提供)：神经调节蛋白(NRG)和ErbB2和ERBB4受体酪氨酸激酶在心脏中的重要性已经得到很好的证实。小鼠的基因缺失实验表明，NeuRegin-1、erbB2和ERBB4是心脏发育所必需的。有条件地敲除erbB2表明，该信号系统是出生后心脏生长和维持正常心脏结构和功能所必需的。基于erbB2抗体的化合物曲妥珠单抗的临床心脏毒性可以解释为证明该系统是心脏对损伤或修复反应所必需的。该研究计划的目标是使用细胞和分子方法详细了解NRG/erbB信号调节心肌结构和功能的机制。在最初的资助阶段，我们已经证明心脏微血管内皮细胞表达一系列复杂的NRG-1亚型，主要是以跨膜蛋白的形式表达。我们进一步证明，NRG-1β亚型在氧化应激条件下被激活，并保护心肌细胞免受几种肌细胞毒性应激源的影响。我们的中心假设是，在应激状态下，心肌neuRegin/erbB信号的激活是动态调节的，以维持心脏的结构和功能。这一假设将通过三个具体目标来实现。目的1将重点介绍微血管内皮细胞蛋白分解过程对NRG激活的调控。目的2将侧重于细胞伴侣和泛素化酶如何调节心肌细胞中erbB2和ERBB4受体的稳定性，从而调节NRG的反应性。目的3将研究NRG如何调节心肌细胞结构，重点是我们最近发现的erbB2受体下游的一个特定的src/FAK通路的作用。最终，这些研究将有助于理解心肌NRG/erbB信号如何发挥积极调节心脏结构、功能和应激反应的作用。

DESCRIPTION (provided by applicant): The importance of Neuregulin (NRG) and the erbB2 and erbB4 receptor tyrosine kinases in the heart is well established. Gene deletion experiments in mice have demonstrated that neuregulin-1, erbB2, and erbB4 are required for cardiac development. Conditional knockout of erbB2 demonstrates that this signaling system is required for postnatal cardiac growth and maintenance of normal cardiac structure and function. Clinical cardiotoxicity of the erbB2 antibody-based compound trastuzumab can be interpreted as a demonstration that this system is required for cardiac response to injury, or repair. The goal of this research program has been to use a cellular and molecular approach to understand in detail the mechanisms by which NRG/erbB signaling functions to regulate myocardial structure and function. In the initial funding period we have demonstrated that cardiac microvascular endothelial cells express a complex array of NRG-1 isoforms, primarily as transmembrane proteins. We have further demonstrated that the NRG-1beta isoform is activated by conditions of oxidative stress and protects cardiac myocytes against several myocytotoxic stressors. Our central hypothesis is that activation of myocardial neuregulin/erbB signaling is dynamically regulated to maintain cardiac structure and function in the setting of stress. This hypothesis will be approached through 3 Specific Aims. Aim 1 will focus on the regulation of NRG activation by proteolytic processing in microvascular endothelial cells. Aim 2 will focus on how cellular chaperones and ubiquitination enzymes regulate erbB2 and erbB4 receptor stability in cardiac myocytes, and therefore NRG responsiveness. Aim 3 will examine how NRG regulates myocyte structure, focusing on the role of a specific src/FAK pathway that we have recently identified downstream of the erbB2 receptor. Ultimately, these studies will lead to an understanding of how myocardial NRG/erbB signaling functions to positively regulate cardiac structure, function, and response to stress.