This applicationis for the renewal of a program project that was initiated in 1986. The proposed research is the outgrowth of the program's progressd uring the current funding period,a nd consists of four projects and two supporting cores focused on the central theme of the structure/function of cardiac glycoside-sensitive proteins. The participating investigators with expertise in membrane biochemistry, protein chemistry, molecular genetics, cell biology,and cardiac physiology/pharmacology will combine their efforts to conduct the following studies: The first Project deals with the characterization of ion pumping and signal transducing functions of a pool of cardiac Na+/K+-ATPase that is localized in the caveolae microdomains of the cell membrane, the cardiacglycoside-induced traffic of signaling proteins into and out of cardiac caveolae, and the functional consequences of this altered traffic. The next Project proposes studies on the structure/function relationship and the reaction mechanism of a humann on-gastric H+/K+-ATPase that is sensitive to cardiac glycosides and is involved in ion homeostasis. Also proposed are studies on the functional characterization of a newly discovered muscle-specific member of the beta-subunit family of P-ATPases. Studies of the next Project are aimed at the identification of organized signaling complexes formed between Na and its close neighbors,the nature of the intermolecular domain interactions, and the cardiac glycoside-induced changes in these interactions and the resulting functions. The final Project proposes studies aimed at the characterization of the mechanisms and the pathways that link cardiac glycoside interaction with Na ATPase to the cardiac mitochondrial KATP channels, and the protective role of these pathways against ischemic damage. The proposed studies are expected to expand knowledge on the biological role of cardiac Na+/K+-ATPase in previously unexplored directions, and to provide new information on the basis of which the therapeutic value of cardiac glycosides as drugs, and their postulated hormonal roles, may be evaluated.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL036573-20
Application #
7194201
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Adhikari, Bishow B
Project Start
1986-07-01
Project End
2009-02-28
Budget Start
2007-03-01
Budget End
2009-02-28
Support Year
20
Fiscal Year
2007
Total Cost
$1,370,176
Indirect Cost
Name
University of Toledo
Department
Physiology
Type
Schools of Medicine
DUNS #
807418939
City
Toledo
State
OH
Country
United States
Zip Code
43614
Duan, Qiming; Xu, Yunhui; Marck, Pauline V et al. (2018) Preconditioning and Postconditioning by Cardiac Glycosides in the Mouse Heart. J Cardiovasc Pharmacol 71:95-103
Duan, Qiming; Xu, Yunhui; Marck, Pauline et al. (2017) Pre- and Post-conditioning by Cardiac Glycosides in the Mouse Heart. J Cardiovasc Pharmacol :
Morrill, Gene A; Kostellow, Adele B; Liu, Lijun et al. (2016) Evolution of the ?-Subunit of Na/K-ATPase from Paramecium to Homo sapiens: Invariance of Transmembrane Helix Topology. J Mol Evol 82:183-98
Wu, Jian; Li, Daxiang; Du, Lingling et al. (2015) Ouabain prevents pathological cardiac hypertrophy and heart failure through activation of phosphoinositide 3-kinase ? in mouse. Cell Biosci 5:64
Duan, Qiming; Madan, Namrata D; Wu, Jian et al. (2015) Role of phosphoinositide 3-kinase IA (PI3K-IA) activation in cardioprotection induced by ouabain preconditioning. J Mol Cell Cardiol 80:114-25
Mehta, Gaurav; Kumarasamy, Sivarajan; Wu, Jian et al. (2015) MITF interacts with the SWI/SNF subunit, BRG1, to promote GATA4 expression in cardiac hypertrophy. J Mol Cell Cardiol 88:101-10
Akkuratov, Evgeny E; Wu, Jian; Sowa, David et al. (2015) Ouabain-Induced Signaling and Cell Survival in SK-N-SH Neuroblastoma Cells Differentiated by Retinoic Acid. CNS Neurol Disord Drug Targets 14:1343-9
Li, Caixia; Culver, Silas A; Quadri, Syed et al. (2015) High-fat diet amplifies renal renin angiotensin system expression, blood pressure elevation, and renal dysfunction caused by Ceacam1 null deletion. Am J Physiol Endocrinol Metab 309:E802-10
Balasubramanian, Priya; Varde, Pratibha A; Abdallah, Simon Labib et al. (2015) Differential effects of prenatal stress on metabolic programming in diet-induced obese and dietary-resistant rats. Am J Physiol Endocrinol Metab 309:E582-8
Gable, Marjorie E; Abdallah, Simon L; Najjar, Sonia M et al. (2014) Digitalis-induced cell signaling by the sodium pump: on the relation of Src to Na(+)/K(+)-ATPase. Biochem Biophys Res Commun 446:1151-4

Showing the most recent 10 out of 247 publications