Role of Neuregulin/erbB Signaling in the Adult Heart

描述（由申请方提供）：已充分确定神经调节蛋白（NRG）以及erbB 2和erbB 4受体酪氨酸激酶在心脏中的重要性。在小鼠中进行的基因缺失实验表明，neuregulin-1、erbB 2和erbB 4是心脏发育所必需的。erbB 2的条件性敲除表明，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erbB 2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的反应所必需的。本研究计划的目标是使用细胞和分子方法来详细了解NRG/erbB信号传导调节心肌结构和功能的机制。在最初的资助期间，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，主要是跨膜蛋白。我们进一步证明了NRG-1 β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因素的影响。我们的中心假设是，心肌neuregulin/erbB信号的激活是动态调节的，以维持心脏结构和功能的压力设置。这个假设将通过三个具体目标来实现。目的1将集中在微血管内皮细胞的蛋白水解过程中的NRG激活的调节。目的2将着重于细胞伴侣和泛素化酶如何调节心肌细胞erbB 2和erbB 4受体的稳定性，从而调节NRG的反应性。目的3将研究NRG如何调节肌细胞结构，重点是我们最近发现的erbB 2受体下游的特定src/FAK通路的作用。最终，这些研究将有助于了解心肌NRG/erbB信号传导如何积极调节心脏结构，功能和应激反应。

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.