This training grant is designed to provide the principal investigator (Pl) with the necessary didactic training and laboratory experience to become an independent biomedical researcher. The PI?s immediate career goals are to acquire the knowledge in using supercomputers and the experimental skills of electrophysiology and microscopy necessary to develop a quantitative understanding of atrial excitation-contraction (E-C) coupling. The Pl?s long-term career goal is to lead a multidisciplinary team of physiologists, mathematicians, physicians, and computer programmers in developing a quantitative understanding of both normal and pathological E-C coupling in atrial cells. Mammalian ventricular cells have an extensive transverse(t)-tubular system that rapidly conducts the action potential from the cell surface to the interior triggering a near synchronous calcium (Ca) release from the sarcoplasmic reticulum (SR) and activation of myofibrils throughout the cell. Atrial cells lack an extensive t-tubular system. How Ca release from the SR far from the cell surface is triggered is unclear. The overall hypothesis is that in atrial cells, Ca entry during an action potential triggers regenerative Ca release from the SR at the cell surface and this regenerative Ca release (""""""""Ca wave"""""""") propagates as a wave radially to the center of the cell.
The Specific Aims are: (1) Test this hypothesis by correlating atrial single-cell contraction rate and magnitude with the Ca wave?s velocity and amplitude using video rate 2-dimensional confocal microscopy and fluorescent Ca indicators. (2) Develop a mathematical model of the atrial cell Ca control system and solve the model numerically using supercomputers. (3) Evaluate the model by comparing the model?s predictions with experimental measurements of Ca waves in voltage-clamped atrial cells using confocal microscopy. A quantitative model of the atrial Ca control system is necessary for understanding both normal E-C coupling and the origins of pathological spontaneous Ca waves, which recent data suggest can trigger atrial arrhythmias.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Mentored Quantitative Research Career Development Award (K25)
Project #
5K25HL068704-02
Application #
6620591
Study Section
Special Emphasis Panel (ZHL1-CSR-M (O2))
Program Officer
Commarato, Michael
Project Start
2002-01-22
Project End
2005-11-30
Budget Start
2002-12-01
Budget End
2003-11-30
Support Year
2
Fiscal Year
2003
Total Cost
$126,948
Indirect Cost
Name
University of Maryland Baltimore
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Banyasz, Tamas; Lozinskiy, Ilya; Payne, Charles E et al. (2008) Transformation of adult rat cardiac myocytes in primary culture. Exp Physiol 93:370-82
Banyasz, Tamas; Chen-Izu, Ye; Balke, C W et al. (2007) A new approach to the detection and statistical classification of Ca2+ sparks. Biophys J 92:4458-65
Chen-Izu, Ye; Chen, Ling; Banyasz, Tamas et al. (2007) Hypertension-induced remodeling of cardiac excitation-contraction coupling in ventricular myocytes occurs prior to hypertrophy development. Am J Physiol Heart Circ Physiol 293:H3301-10
Izu, Leighton T; Banyasz, Tamas; Balke, C William et al. (2007) Eavesdropping on the social lives of Ca(2+) sparks. Biophys J 93:3408-20
Chen-Izu, Ye; Ward, Christopher W; Stark Jr, Wayne et al. (2007) Phosphorylation of RyR2 and shortening of RyR2 cluster spacing in spontaneously hypertensive rat with heart failure. Am J Physiol Heart Circ Physiol 293:H2409-17
Izu, Leighton T; Means, Shawn A; Shadid, John N et al. (2006) Interplay of ryanodine receptor distribution and calcium dynamics. Biophys J 91:95-112
Chen-Izu, Ye; McCulle, Stacey L; Ward, Chris W et al. (2006) Three-dimensional distribution of ryanodine receptor clusters in cardiac myocytes. Biophys J 91:1-13
Kirk, Malcolm M; Izu, Leighton T; Chen-Izu, Ye et al. (2003) Role of the transverse-axial tubule system in generating calcium sparks and calcium transients in rat atrial myocytes. J Physiol 547:441-51