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 #
2R01HL068144-05A1
Application #
7099965
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Liang, Isabella Y
Project Start
2001-09-30
Project End
2006-06-30
Budget Start
2006-04-01
Budget End
2006-06-30
Support Year
5
Fiscal Year
2006
Total Cost
$124,579
Indirect Cost
Name
Boston Medical Center
Department
Type
DUNS #
005492160
City
Boston
State
MA
Country
United States
Zip Code
02118
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
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
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
Odiete, Oghenerukevwe; Hill, Michael F; Sawyer, Douglas B (2012) Neuregulin in cardiovascular development and disease. Circ Res 111:1376-85
Chen, Billy; Zhong, Lin; Roush, Sarah F et al. (2012) Disruption of a GATA4/Ankrd1 signaling axis in cardiomyocytes leads to sarcomere disarray: implications for anthracycline cardiomyopathy. PLoS One 7:e35743
Cote, Gregory M; Sawyer, Douglas B; Chabner, Bruce A (2012) ERBB2 inhibition and heart failure. N Engl J Med 367:2150-3

Showing the most recent 10 out of 37 publications