The Ventricular and Cardiac Fiber Characterization and Integration Core (Core B) will serve to characterize and integrate the mechanical consequences of MyBP-C phosphorylation and actin-binding on the working mouse left ventricle (LV) and the chemically-skinned cardiac fiber: In vivo phenotypic characterization of mouse LV will be performed by Drs. Kass and Takimoto at Johns Hopkins University using a miniaturized volume conductance catheter system to record LV pressure-volume loops under near physiological conditions. These measures will result in a variety of sophisticated parameters of mouse LV systolic and diastolic function, which relate to similar parameters in humans. In vitro phenotypic characterization of cardiac myofilaments will be assessed by Drs. Palmer and Maughan at the University of Vermont using a variety of mechanical assays in the chemically-skinned cardiac fiber preparation. The measurements made in the LV and cardiac fiber will serve to provide data, which directly test specific hypotheses raised in Projects #2-Warshaw/VanBuren and #3-Robbins. These hypotheses are (i) the mechanical consequences of MyBP-C phosphorylation requires phosphorylation of specific sites and/or sequence of sites, (ii) that the N-terminus of MyBP-C interacts with actin and can affect thin filament activation and/or impart a mechanical load on the sarcomere, and (iii) MyBP-C phosphorylation and/or actin interaction modifies acto-myosin kinetics such as myosin time-on. Several measures made in the Core at the myofilament level, -including myosin time-on, are expected to correlate directly to those made by Project #2-Warshaw/VanBuren at the single-molecule level. The integration portion of this Core will demonstrate the relevance of mechanical measures found at the molecular level to the geometry of the myofilament lattice of the cardiac fiber and the working LV. The investigations undertaken in this Core will then be coordinated and compared with the intent to systematically integrate findings at the molecular level (Project #2-Warshaw/VanBuren) with those measures of mechanical performance at the myofilament and ventricular levels (Project #3-Robbins).

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL059408-12
Application #
8215312
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
2011-02-01
Project End
2015-01-31
Budget Start
2011-02-01
Budget End
2012-01-31
Support Year
12
Fiscal Year
2011
Total Cost
$495,529
Indirect Cost
Name
University of Vermont & St Agric College
Department
Type
DUNS #
066811191
City
Burlington
State
VT
Country
United States
Zip Code
05405
Kensler, Robert W; Craig, Roger; Moss, Richard L (2017) Phosphorylation of cardiac myosin binding protein C releases myosin heads from the surface of cardiac thick filaments. Proc Natl Acad Sci U S A 114:E1355-E1364
McLendon, Patrick M; Davis, Gregory; Gulick, James et al. (2017) An Unbiased High-Throughput Screen to Identify Novel Effectors That Impact on Cardiomyocyte Aggregate Levels. Circ Res 121:604-616
Gupta, Manish K; McLendon, Patrick M; Gulick, James et al. (2016) UBC9-Mediated Sumoylation Favorably Impacts Cardiac Function in Compromised Hearts. Circ Res 118:1894-905
Mun, Ji Young; Kensler, Robert W; Harris, Samantha P et al. (2016) The cMyBP-C HCM variant L348P enhances thin filament activation through an increased shift in tropomyosin position. J Mol Cell Cardiol 91:141-7
Tewari, Shivendra G; Bugenhagen, Scott M; Palmer, Bradley M et al. (2016) Dynamics of cross-bridge cycling, ATP hydrolysis, force generation, and deformation in cardiac muscle. J Mol Cell Cardiol 96:11-25
Yang, Shixin; Woodhead, John L; Zhao, Fa-Qing et al. (2016) An approach to improve the resolution of helical filaments with a large axial rise and flexible subunits. J Struct Biol 193:45-54
Previs, Michael J; Mun, Ji Young; Michalek, Arthur J et al. (2016) Phosphorylation and calcium antagonistically tune myosin-binding protein C's structure and function. Proc Natl Acad Sci U S A 113:3239-44
Bhuiyan, Md Shenuarin; McLendon, Patrick; James, Jeanne et al. (2016) In vivo definition of cardiac myosin-binding protein C's critical interactions with myosin. Pflugers Arch 468:1685-95
Warshaw, David M (2016) HEART DISEASE. Throttling back the heart's molecular motor. Science 351:556-7
James, Jeanne; Robbins, Jeffrey (2016) Healing a Heart Through Genetic Intervention. Circ Res 118:920-2

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