Our long-term objective is to understand the relative role of Ca2+ and myofilaments in the regulation of cardiac function under normal and pathological conditions such as hypertrophy and heart failure (HF). In the current proposal we will focus on genetically linked hypertrophy, hypertrophic cardiomyopathy (HCM). We hypothesize that if HCM is associated with increased myofilament sensitivity to Ca2+ and diastolic dysfunction, then pathological cardiac hypertrophy and cardiac dysfunction can be delayed or prevented by short and long-term interventions in Ca2+ regulation. We also hypothesize that the increased myofilament sensitivity to Ca2+ that is observed in HCM is also associated with alterations in beta-adrenergic receptor mediated pathways resulting in altered myofilament and sarcoplasmic reticulum (SR) protein phosphorylation, which are all important elements in the development of hypertrophy and HF in general. We will test the hypothesis that increasing SR Ca2+ uptake by increased expression of SR Ca2+ pump (SERCA2a;
Aim 1) or by phospholamban knockout (Aim 2) will delay the development of hypertrophy and improve heart function in HCM linked mutations in regulatory proteins such as tropomyosin (TM) or troponin T (TnT) that show increased myofilament sensitivity to Ca2+ and diastolic dysfunction.
In Aim 3 we will determine the role of altered myofilament and sarcoplasmic reticulum beta-adrenergic receptor mediated protein phosphorylation in the development of hypertrophy in the same HCM linked mutations in regulatory proteins. In summary we seek to better understand the role of increased myofilament sensitivity to Ca2+ in development of hypertrophy in HCM and to test the hypothesis that increasing SR Ca2+ uptake my overcome the increased myofilament sensitivity to Ca2+, restore normal diastolic function, and in the long term delay the development of hypertrophy and cardiac dysfunction. Therefore, the current proposal may have potential clinical applications. ? ?
Showing the most recent 10 out of 18 publications