Hypertrophy is a characteristic response of the terminally differentiated cardiac myocyte to growth stimuli. A cascade of intracellular signaling processes, largely defined in neonatal cardiocytes, has been proposed to mediated features of this response, a central component of which is activation of protein kinase C. In previous work, the investigators have developed a novel transgenic model which allows conditional expression of a protein kinase C isoform in the murine heart and they have established that expression and activation of the isoform is sufficient to effect distinct developmental stage specific adaptations: PKC Beta expression in neonates causes death and is associated with abnormal myocardiocyte calcium regulation whereas in adults, expression of the transgene is associated with regulation whereas in adults, expression of the transgene is associated with concentric cardiac hypertrophy, impaired mechanical performance and relative resistance to ischemia. Having confirmed the feasibility of this approach, the focus of the current proposal, the focus of the current proposal will be to identify roles for specific isoforms of protein kinase C (beta and epsilon) and to define which specific targets of PKC are responsible for the observed adaptations. Both gain and loss of function will be recapitulated in transgenic models and analysis of the functional effects of PKC expression will be at the level of the whole heart and also at the cellular level. Factors which influence calcium flux and myofilament calcium sensitivity will be evaluated. A unique feature of the project is the use of conditional transgenesis which allows assessment of the physiologic and the biochemical effects of gene activation in the heart at different developmental stages and while it os on the process of altering its phenotypes. This provides a unique and powerful tool to investigate causality.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL062426-02
Application #
6460240
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
2001-06-01
Project End
2002-05-31
Budget Start
Budget End
Support Year
2
Fiscal Year
2001
Total Cost
$281,209
Indirect Cost
Name
University of Illinois at Chicago
Department
Type
DUNS #
121911077
City
Chicago
State
IL
Country
United States
Zip Code
60612
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