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. ? ? ?
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