The theme continues to be the identification of factors that govern the efficiency of ATP synthesis, utilization, and the maintenance of ion gradients in the myocardium. The interconversion between chemical and ion gradient energy is very highly coupled in myocardial cells, thus imbalances between energy supply and demand are unforgiving. The rationale is to provide novel physiological concepts which are at the core of understanding the development and prevention of myocardial disease occurring from insufficient chemical energy supply (ischemic heart), imbalance between ATP production and utilization (hypertrophy heart), or derangement of signaling or ion gradients (arrhythmia). This Program consists of 4 components. The titles are: Novel Regulation of Cellular Mg2+ and Ca2+ Homeostasis in the Heart. Release and Metabolism of Extracellular ATP in the Heart: Crosstalk between Cardiac Bioenergetics and Signal Transduction. Thyroidal Regulation of Na+, K+-ATPase Expression and Energetics of the Heart. Time-resolved X-ray Interferometry Studies of the Sarcoplasmic Reticulum Calcium ATPase. Some of the broad integrated questions to be addressed in this application are: how does catecholamine-induced redistribution of Mg2+ between tissue and plasma modulate ATPases and cellular ion content?; how do extracellular ATP molecules and Mg2+ produce signals in the heart which result in adenosine formation, PKC signaling and redistribution of ions?""""""""; how does thyroid hormone, through specific regulation of the Na+-K+ ATPase expression and creatine transport increase ATP synthesis and utilization while decreasing the maximal energetic capacity of the myocardium?; how, through the brightest x-ray sources coupled with a novel detection system, it is possible to correlate kinetically profiled structures of the various intermediate states of the SR Ca2+ ATPase and Ca2+ location during catalysis?. The major strength of this Program is the convergence of important aspects of myocardial function by several established and interactive researchers, bringing to the theme a broad repertoire of unique expertise. A major revision occurred in Projects 1 and 3, while Projects 2 and 4 have been nearly entirely rewritten.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
2P01HL018708-26A1
Application #
6423619
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Balshaw, David M
Project Start
1976-04-01
Project End
2006-12-31
Budget Start
2002-02-15
Budget End
2002-12-31
Support Year
26
Fiscal Year
2002
Total Cost
$1,219,695
Indirect Cost
Name
Case Western Reserve University
Department
Physiology
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Cefaratti, C; Romani, A (2011) Modulation of Na+/Mg²+ exchanger stoichiometry ratio by Cl? ions in basolateral rat liver plasma membrane vesicles. Mol Cell Biochem 351:133-42
Prosdocimo, Domenick A; Wyler, Steven C; Romani, Andrea M et al. (2010) Regulation of vascular smooth muscle cell calcification by extracellular pyrophosphate homeostasis: synergistic modulation by cyclic AMP and hyperphosphatemia. Am J Physiol Cell Physiol 298:C702-13
Dubyak, George R (2009) Both sides now: multiple interactions of ATP with pannexin-1 hemichannels. Focus on ""A permeant regulating its permeation pore: inhibition of pannexin 1 channels by ATP"". Am J Physiol Cell Physiol 296:C235-41
Prosdocimo, Domenick A; Douglas, Dezmond C; Romani, Andrea M et al. (2009) Autocrine ATP release coupled to extracellular pyrophosphate accumulation in vascular smooth muscle cells. Am J Physiol Cell Physiol 296:C828-39
Kasturi, Sriram; Ismail-Beigi, Faramarz (2008) Effect of thyroid hormone on the distribution and activity of Na, K-ATPase in ventricular myocardium. Arch Biochem Biophys 475:121-7
Blum, Andrew E; Joseph, Sheldon M; Przybylski, Ronald J et al. (2008) Rho-family GTPases modulate Ca(2+) -dependent ATP release from astrocytes. Am J Physiol Cell Physiol 295:C231-41
Ballard, Brandon; Torres, Lisa M; Romani, Andrea (2008) Effect of thyroid hormone on Mg(2+) homeostasis and extrusion in cardiac cells. Mol Cell Biochem 318:117-27
Marengo, Susan R; Romani, Andrea M P (2008) Oxalate in renal stone disease: the terminal metabolite that just won't go away. Nat Clin Pract Nephrol 4:368-77
Reed, Grant; Cefaratti, Christie; Berti-Mattera, Liliana N et al. (2008) Lack of insulin impairs Mg2+ homeostasis and transport in cardiac cells of streptozotocin-injected diabetic rats. J Cell Biochem 104:1034-53
Cefaratti, Christie; Romani, Andrea M P (2007) Functional characterization of two distinct Mg(2+) extrusion mechanisms in cardiac sarcolemmal vesicles. Mol Cell Biochem 303:63-72

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