Decreased SERCA pump expression and activity have been implicated in diastolic dysfunction and heart failure. To better define the role of decreased SERCA pump expression we developed a SERCA2 gene knockout (-/+) model. However, heterozygous mice (born with only a single functional allele of the SERCA2 gene) induce several compensatory alterations in expression and activity of other Ca2+ handling proteins to make up a decrease in SERCA pump function. Thus, a chronic reduction in SERCA2 activity results in a new equilibrium set point for the regulation of cardiomyocyte Ca2+ homeostasis. To overcome this problem we will develop a Conditional knockout (cKO) mouse model to ablate the SERCA2 gene in a heart specific and inducible manner in adult stages. Studies also indicate that SERCA2a and 2b are co-expressed in the heart and SERCA2b can substitute for SERCA2a function. Compared with SERCA2a, SERCA2b has 49 extra C-terminal amino acids and has a higher Ca2+ affinity and lower turnover rate. We hypothesize that SERCA2b plays a unique role in SR Ca2+ uptake (because of its high apparent affinity for Ca2+ ion) and is important for maintaining low cytosolic Ca2+ content. To define the role of SERCA2b we will use adenoviral-mediated SERCA gene transfer into adult rat myocytes. In addition, we have preliminary data to suggest that SERCA protein either forms a complex or co-localizes with its regulatory molecules (PLB, sarcolipin, PKA, CaMKII, Phosphatase 1 and 2a, tethered via anchoring molecules) for efficient regulation of SR Ca2+ uptake function. In this proposal we seek to identify the SERCA macromolecular complex using immuno-precipitations and 2D gel analyses and MASS spectrometry. Collectively, these studies will allow us to better understand the role of SERCA2a and 2b pumps in the beat-to-beat function of the myocardium. As such, these studies are likely to suggest novel clinical strategies that might be pursued for the management of chronic heart failure in humans. ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL064140-08
Application #
7000381
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Program Officer
Przywara, Dennis
Project Start
2000-01-15
Project End
2007-12-31
Budget Start
2006-01-01
Budget End
2006-12-31
Support Year
8
Fiscal Year
2006
Total Cost
$364,967
Indirect Cost
Name
Ohio State University
Department
Physiology
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Xie, Lin; Talukder, M A Hassan; Sun, Jian et al. (2015) Liposomal tetrahydrobiopterin preserves eNOS coupling in the post-ischemic heart conferring in vivo cardioprotection. J Mol Cell Cardiol 86:14-22
Kumar, Amit; Chakravarty, Harapriya; Bal, Naresh C et al. (2013) Identification of calcium binding sites on calsequestrin 1 and their implications for polymerization. Mol Biosyst 9:1949-57
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Talukder, M A Hassan; Yang, Fuchun; Nishijima, Yoshinori et al. (2011) Detrimental effects of thyroid hormone analog DITPA in the mouse heart: increased mortality with in vivo acute myocardial ischemia-reperfusion. Am J Physiol Heart Circ Physiol 300:H702-11
Zweier, Jay L; Talukder, M A Hassan (2011) Targeting dimethylarginine dimethylaminohydrolases in pulmonary arterial hypertension: a new approach to improve vascular dysfunction? Circulation 123:1156-8
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Talukder, M A Hassan; Zweier, Jay L; Periasamy, Muthu (2009) Targeting calcium transport in ischaemic heart disease. Cardiovasc Res 84:345-52
Talukder, M A Hassan; Yang, Fuchun; Nishijima, Yoshinori et al. (2009) Reduced SERCA2a converts sub-lethal myocardial injury to infarction and affects postischemic functional recovery. J Mol Cell Cardiol 46:285-7
Gupta, Subash C; Varian, Kenneth D; Bal, Naresh C et al. (2009) Pulmonary artery banding alters the expression of Ca2+ transport proteins in the right atrium in rabbits. Am J Physiol Heart Circ Physiol 296:H1933-9
Bhupathy, Poornima; Babu, Gopal J; Ito, Makoto et al. (2009) Threonine-5 at the N-terminus can modulate sarcolipin function in cardiac myocytes. J Mol Cell Cardiol 47:723-9

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