: The broad objective of this application is to determine the molecular mechanisms behind alpha-MHC down-regulation that occurs during heart failure. Recent data obtained from both animals and humans indicate a considerable loss of alpha-MHC gene product. However, the mechanism behind alpha-MHC down-regulation during heart failure remains virtually unknown. Recently, the PI has cloned and characterized a single-strand DNA-binding protein (PNRB) that plays a repressor role in gene transcription. Interestingly, the PI found that PNRB binds not only to an essential cis-regulatory element of the alpha-MHC gene but also to the coding region of alpha-MHC mRNA. The RNA oligonucleotide corresponding to this coding region has the ability to specifically pull down PNRB from cardiac nuclear extract. Furthermore, cellular levels of PNRB are found to be tremendously high in failing hearts. In light of these observations, the PI believes that PNRB plays a dual role, impairing both transcription and translational regulation of alpha-MHC gene expression in overloaded hearts. In this proposal, experiments have been designed to further explore the significance of PNRB in the control of alpha-MHC expression during heart failure. The PI will examine the role of PNRB in the transcription and translation of the alpha-MHC-reporter gene. The PI will also analyze the physiological significance of PNRB in alpha-MHC expression in a while heart preparation, and on the contractile characteristics of a failing heart.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL068083-01
Application #
6367774
Study Section
Cardiovascular and Renal Study Section (CVB)
Program Officer
Reinlib, Leslie
Project Start
2001-09-30
Project End
2005-07-31
Budget Start
2001-09-30
Budget End
2002-07-31
Support Year
1
Fiscal Year
2001
Total Cost
$302,000
Indirect Cost
Name
University of Chicago
Department
Surgery
Type
Schools of Medicine
DUNS #
225410919
City
Chicago
State
IL
Country
United States
Zip Code
60637
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Sundaresan, Nagalingam R; Gupta, Madhu; Kim, Gene et al. (2009) Sirt3 blocks the cardiac hypertrophic response by augmenting Foxo3a-dependent antioxidant defense mechanisms in mice. J Clin Invest 119:2758-71
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Pillai, Jyothish B; Gupta, Madhu; Rajamohan, Senthilkumar B et al. (2006) Poly(ADP-ribose) polymerase-1-deficient mice are protected from angiotensin II-induced cardiac hypertrophy. Am J Physiol Heart Circ Physiol 291:H1545-53
Pillai, Jyothish B; Russell, Hyde M; Raman, Jai et al. (2005) Increased expression of poly(ADP-ribose) polymerase-1 contributes to caspase-independent myocyte cell death during heart failure. Am J Physiol Heart Circ Physiol 288:H486-96
Davis, Francesca J; Pillai, Jyothish B; Gupta, Madhu et al. (2005) Concurrent opposite effects of trichostatin A, an inhibitor of histone deacetylases, on expression of alpha-MHC and cardiac tubulins: implication for gain in cardiac muscle contractility. Am J Physiol Heart Circ Physiol 288:H1477-90

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