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. ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL079032-04
Application #
7406591
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Przywara, Dennis
Project Start
2005-06-01
Project End
2010-04-30
Budget Start
2008-05-01
Budget End
2010-04-30
Support Year
4
Fiscal Year
2008
Total Cost
$310,601
Indirect Cost
Name
University of Illinois at Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Alves, Marco L; Dias, Fernando A L; Gaffin, Robert D et al. (2014) Desensitization of myofilaments to Ca2+ as a therapeutic target for hypertrophic cardiomyopathy with mutations in thin filament proteins. Circ Cardiovasc Genet 7:132-143
Rajan, Sudarsan; Pena, James R; Jegga, Anil G et al. (2013) Microarray analysis of active cardiac remodeling genes in a familial hypertrophic cardiomyopathy mouse model rescued by a phospholamban knockout. Physiol Genomics 45:764-73
Lai, Hsiao-Lei; Grachoff, Milana; McGinley, Andrea L et al. (2012) Maintenance of adult cardiac function requires the chromatin factor Asxl2. J Mol Cell Cardiol 53:734-41
DeSantiago, J; Bare, D J; Semenov, I et al. (2012) Excitation-contraction coupling in ventricular myocytes is enhanced by paracrine signaling from mesenchymal stem cells. J Mol Cell Cardiol 52:1249-56
Gaffin, Robert D; Peña, James R; Alves, Marco S L et al. (2011) Long-term rescue of a familial hypertrophic cardiomyopathy caused by a mutation in the thin filament protein, tropomyosin, via modulation of a calcium cycling protein. J Mol Cell Cardiol 51:812-20
Sheehan, Katherine A; Arteaga, Grace M; Hinken, Aaron C et al. (2011) Functional effects of a tropomyosin mutation linked to FHC contribute to maladaptation during acidosis. J Mol Cell Cardiol 50:442-50
Louch, William E; Sheehan, Katherine A; Wolska, Beata M (2011) Methods in cardiomyocyte isolation, culture, and gene transfer. J Mol Cell Cardiol 51:288-98
Gaffin, Robert D; Chowdhury, Shamim A K; Alves, Marco S L et al. (2011) Effects of nicotine administration in a mouse model of familial hypertrophic cardiomyopathy, ýý-tropomyosin D175N. Am J Physiol Heart Circ Physiol 301:H1646-55
Peña, James R; Szkudlarek, Ariani C; Warren, Chad M et al. (2010) Neonatal gene transfer of Serca2a delays onset of hypertrophic remodeling and improves function in familial hypertrophic cardiomyopathy. J Mol Cell Cardiol 49:993-1002
Dias, Fernando A L; Urboniene, Dalia; Yuzhakova, Milana A et al. (2010) Ablation of iNOS delays cardiac contractile dysfunction in chronic hypertension. Front Biosci (Elite Ed) 2:312-24

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