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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL068144-09
Application #
7598915
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Schwartz, Lisa
Project Start
2001-09-30
Project End
2011-03-31
Budget Start
2009-04-02
Budget End
2011-03-31
Support Year
9
Fiscal Year
2009
Total Cost
$327,478
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Rath, Rutwik; Lee, Jung Bok; Tran, Truc-Linh et al. (2016) Biomimetic microstructure morphology in electrospun fiber mats is critical for maintaining healthy cardiomyocyte phenotype. Cell Mol Bioeng 9:107-115
Lenneman, Carrie G; Abdallah, Wissam M; Smith, Holly M et al. (2014) Sympathetic nervous system alterations with HER2+ antagonism: an early marker of cardiac dysfunction with breast cancer treatment? Ecancermedicalscience 8:446
Hill, Michael F; Patel, Amish V; Murphy, Abigail et al. (2013) Intravenous glial growth factor 2 (GGF2) isoform of neuregulin-1? improves left ventricular function, gene and protein expression in rats after myocardial infarction. PLoS One 8:e55741
Geisberg, Carrie A; Abdallah, Wissam M; da Silva, Monica et al. (2013) Circulating neuregulin during the transition from stage A to stage B/C heart failure in a breast cancer cohort. J Card Fail 19:10-5
Odiete, Oghenerukevwe; Konik, Ewa A; Sawyer, Douglas B et al. (2013) Type 1 diabetes mellitus abrogates compensatory augmentation of myocardial neuregulin-1?/ErbB in response to myocardial infarction resulting in worsening heart failure. Cardiovasc Diabetol 12:52
Lenneman, Andrew J; Wang, Li; Wigger, Mark et al. (2013) Heart transplant survival outcomes for adriamycin-dilated cardiomyopathy. Am J Cardiol 111:609-12
Pentassuglia, Laura; Sawyer, Douglas B (2013) ErbB/integrin signaling interactions in regulation of myocardial cell-cell and cell-matrix interactions. Biochim Biophys Acta 1833:909-16
Cote, Gregory M; Sawyer, Douglas B; Chabner, Bruce A (2012) ERBB2 inhibition and heart failure. N Engl J Med 367:2150-3
Icli, Basak; Bharti, Ajit; Pentassuglia, Laura et al. (2012) ErbB4 localization to cardiac myocyte nuclei, and its role in myocyte DNA damage response. Biochem Biophys Res Commun 418:116-21
Samaras, Susan E; Chen, Billy; Koch, Stephen R et al. (2012) 26S proteasome regulation of Ankrd1/CARP in adult rat ventricular myocytes and human microvascular endothelial cells. Biochem Biophys Res Commun 425:830-5

Showing the most recent 10 out of 37 publications