The long-range goal of this proposal is to identify, develop, and implement new experimental strategies that target improvement in diastolic performance in the failing myocardium. Health relevance derives from our focus on diastolic heart failure, which is a significant and growing medical problem in this country. There are few clinically effective treatments for diastolic heart failure, underscoring the relevance of this research to public health. We recently identified the Ca2+ binding protein parvalbumin (Parv) as a unique candidate to correct diastolic dysfunction in failing hearts. We showed that a key feature of Parv resides in the rather delicate trade-off between improvements in relaxation performance and diminution in contractility. This proposal will investigate two new strategies to correct diastolic dysfunction while retaining systolic performance. Two proteins demonstrated recently to improve Ca2+ release from the sarcoplasmic reticulum (SR) and enhance systolic function, but not diastolic function, are S100A1 and Sorcin. In complementary experiments, we will implement and test Parv isoforms and mutant Parvs that have biochemically determined variations in Mg2+ /Ca2+ binding affinities, to assess whether these novel Ca2+ buffers could correct diastolic dysfunction and preserve systolic performance.
The Specific Aims are:
Aim 1. To determine if dual gene transfer of Parv with either S100A1 or Sorcin will hasten relaxation performance and enhance contractility in adult cardiac myocytes in vitro. Hypothesis: Co-gene transfer of Parv with S100A1 or Sorcin will accelerate relaxation rate while maintaining or enhancing contractility in normal and failing myocytes.
Aim 2. To test the contractile effects of Parv isoforms and mutants that have naturally occurring or engineered modifications in E-F hand Ca2+/Mg2+ binding affinities in myocytes in vitro. Hypothesis: Compared to wild-type alpha-Parv, Parv isoforms/mutants with biochemically determined increases in Mg2+ binding affinity will hasten relaxation performance without compromising contractility, even at high [ Parv] (0.5 mM).
Aim 3. To use recombinant adeno-associated vectors (AAV6) for efficient (near 100% cardiac myocytes) and stable (months) expression of wild-type and modified Parvs in vivo. Hypothesis: Parvs with heightened Mg2+ affinities relative to wild-type Parv will enhance long-term diastolic performance and preserve systolic performance in the failing heart in vivo.
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