Heart failure is characterized by a number of abnormalities at the cellular level in the various steps of excitation-contraction coupling. One of the key abnormalities in both human and experimental heart failure is a defect in sarcoplasmic reticulum (SR) function which is associated with abnormal intracellular calcium handling. Deficient SR Ca2+ uptake during relaxation has been identified in failing hearts from both humans and animal models and has been associated with a decrease in the expression and activity of SR Ca2+-ATPase (SERCA2a). The goals of the First Award (R29) were 1) to validate the use of adenoviral gene transfer in the rat model of heart failure and 2) to test the hypothesis that increasing the expression of SERCA2a will restore contractility and normalize intracellular calcium cycling in this model of heart failure. These goals have been specifically achieved during the tenure of the grant. To further extend these results that have clinical promise for the treatment of congestive heart failure, we will test the following hypotheses: 1) that the long-term overexpression of SERCA2a will improve survival and induce ventricular and metabolic remodeling in a rat model of heart failure; 2) overexpression of SERCA2a during compensated hypertrophv will delay the onset of the transition to heart failure; 3) decreasing phospholamban expression by antisense strategies will enhance SR Ca2+ATPase function in failing hearts and restore function, and 4) the beneficial effect observed by improving calcium handling in heart failure is specific to SERCA2a. To test these hypotheses, we will use viral vectors to express wild-type and mutant forms of specific signaling molecules in cardiocytes in vitro and in vivo.
In Specific Aim 1, we will develop and characterize ventricular specific vectors carrying SERCA2a and transduce ventricles from hypertrophied and failing rat hearts.
In Specific Aim 2, we will examine the effects of decreasing phospholamban using antisense strategies on survival and remodeling in hypertrophied and failing rat hearts.
In Specific Aim 3, we will study the effect of improving calcium handling in failing rat hearts by overexpressing Na+/Ca2+ exchanger and parvalbumin in a rat model of heart failure. Understanding the role of calcium regulation in cardiocyte dysfunction and developing approaches to local modulation of these pathways through somatic gene transfer, may provide novel therapeutic approaches for the management of heart failure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL057263-08
Application #
6881289
Study Section
Pharmacology A Study Section (PHRA)
Program Officer
Evans, Frank
Project Start
1997-02-10
Project End
2006-03-31
Budget Start
2005-04-01
Budget End
2006-03-31
Support Year
8
Fiscal Year
2005
Total Cost
$432,500
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
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