) The applicant's long term career goal is to contribute at a basic level to our understanding of the molecular mechanisms of heart failure. His short term career objectives are: 1) to gain insight into and learn techniques available for the measurement and manipulation of reactive oxygen species (ROS) in living systems; 2) use various molecular biological techniques for the manipulation and measurement of transcriptional events in cultured myocytes; 3) and then use in vivo animal models of myocardial injury and transgenic animals to test hypotheses developed in culture systems. The candidate received his Ph.D. in 1990 studying lipid protein interactions using single channel electrophysiology, and has spent the last 5 years at Brigham and Women's Hospital completing my clinical training in internal medicine and cardiology. There he began to study the mechanisms of ROS mediated myocardial injury, specifically, programmed cell death. He recently moved to Boston Medical Center to continue these efforts. The particular interest of cardiology and medicine faculty there in ROS provides a fertile environment for him to develop his scientific ideas. The hypotheses he will test are that ROS, in particular superoxide anion and/or hydroxyl radicals, can trigger apoptosis in ventricular myocytes, and that myocytes are able to regulate their susceptibility to these species by transcriptional regulation of cytotoxic defense systems. Firstly, he will use cultured adult and neonatal rat ventricular myocytes to examine exactly which ROS can induce apoptosis in cultured myocytes. Secondly, he will examine whether preconditioning stimuli can increase activities of specific cytotoxic defense systems and in this way prevent ROS-mediated apoptosis in ventricular myocytes. Thirdly, using an adenovirus transfection system, he will study whether over-expression of superoxide dismutase or catalase can protect against ROS-Induced apoptosis in cardiac myocytes. Finally, he will examine whether transgenic mice over-expressing manganese-dependent superoxide dismutase have increased susceptibility to myocardial apoptosis after myocardial infarction.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL003878-05
Application #
6536529
Study Section
Special Emphasis Panel (ZHL1-CSR-Y (M2))
Program Officer
Commarato, Michael
Project Start
1998-07-15
Project End
2003-06-30
Budget Start
2002-07-01
Budget End
2003-06-30
Support Year
5
Fiscal Year
2002
Total Cost
$114,129
Indirect Cost
Name
Boston Medical Center
Department
Type
DUNS #
005492160
City
Boston
State
MA
Country
United States
Zip Code
02118
Sawyer, Douglas B (2011) Oxidative stress in heart failure: what are we missing? Am J Med Sci 342:120-4
Kuramochi, Yukio; Guo, Xinxin; Sawyer, Douglas B et al. (2006) Rapid electrical stimulation induces early activation of kinase signal transduction pathways and apoptosis in adult rat ventricular myocytes. Exp Physiol 91:773-80
Kuramochi, Yukio; Lim, Chee Chew; Guo, Xinxin et al. (2004) Myocyte contractile activity modulates norepinephrine cytotoxicity and survival effects of neuregulin-1beta. Am J Physiol Cell Physiol 286:C222-9
Maytin, Melanie; Siwik, Deborah A; Ito, Masahiro et al. (2004) Pressure overload-induced myocardial hypertrophy in mice does not require gp91phox. Circulation 109:1168-71
Lim, Chee Chew; Zuppinger, Christian; Guo, Xinxin et al. (2004) Anthracyclines induce calpain-dependent titin proteolysis and necrosis in cardiomyocytes. J Biol Chem 279:8290-9
Jain, Mohit; Brenner, Daniel A; Cui, Lei et al. (2003) Glucose-6-phosphate dehydrogenase modulates cytosolic redox status and contractile phenotype in adult cardiomyocytes. Circ Res 93:e9-16
Fukazawa, Ryuji; Miller, Thomas A; Kuramochi, Yukio et al. (2003) Neuregulin-1 protects ventricular myocytes from anthracycline-induced apoptosis via erbB4-dependent activation of PI3-kinase/Akt. J Mol Cell Cardiol 35:1473-9
Remondino, Andrea; Kwon, Susan H; Communal, Catherine et al. (2003) Beta-adrenergic receptor-stimulated apoptosis in cardiac myocytes is mediated by reactive oxygen species/c-Jun NH2-terminal kinase-dependent activation of the mitochondrial pathway. Circ Res 92:136-8
Helmes, Michiel; Lim, Chee Chew; Liao, Ronglih et al. (2003) Titin determines the Frank-Starling relation in early diastole. J Gen Physiol 121:97-110
Kwon, Susan H; Pimentel, David R; Remondino, Andrea et al. (2003) H(2)O(2) regulates cardiac myocyte phenotype via concentration-dependent activation of distinct kinase pathways. J Mol Cell Cardiol 35:615-21

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