Cardiac excitation-contraction is tightly coupled (EC)via the L-voltage-dependent Ca2+ Channel supplying the required Ca2+ ingress with each beat to initiate contraction. Calcium is the cation that serves as the link between depolarization and contraction. We have been studying the complex architecture and regulation that comprises the L-VDCC, the subunits of which include the alphalC, beta and the alpha2/delta, employing transgenic approaches rather than heterologous systems. In this manner, we are able to delineate in vivo function. Transgenic remodeling of the channel subunits in the heart is not only a convenient way to determine and alter subunit stoichoimetry in vivo, but it provides a model for studying cardiac dysfunction related to calcium. The long-term objective is to characterize the in vivo regulation of the L-voltage-dependent Ca2+ Channel, in terms of calcium regulation. In this revised application, we emphasize the in vivo roles of the pore unit (i.e., the alphalC), the beta- and the alpha2/delta1 subunits in regulation of the pore unit in normal and cardiac hypertrophy/failure in the mouse and human heart. A knockout strategy of the alpha2/delta1 should yield significant and detailed information on regulation of the pore unit in normal heart and possibly in heart failure. These transgenic approaches should provide new information regarding how the the L-VDCC functions in vivo , and how each of the associated subunits contributes to the regulation of the pore unit. Hopefully ,the data will be useful in eventually designing rational pharmacotherapeutic and genetic prevention/treatment strategies.
The Specific Aims are: Transgenic remodeling of and delineating in vivo roles for subunit composition of mouse myocardium of L-voltage-dependent Ca2+ Channels: 1) Characterization of the alphalC subunit: molecular mechanisms of cardiac hypertrophy/failure. 2) Roles of the beta-subunits;3) Knockout of the alpha2/delta~ subunit.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL079599-04
Application #
7585164
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Przywara, Dennis
Project Start
2006-04-15
Project End
2011-03-31
Budget Start
2009-04-01
Budget End
2011-03-31
Support Year
4
Fiscal Year
2009
Total Cost
$369,957
Indirect Cost
Name
University of Cincinnati
Department
Surgery
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
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