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 #
5P01HL059408-15
Application #
8611950
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
2016-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
15
Fiscal Year
2014
Total Cost
$905,561
Indirect Cost
$171,018
Name
University of Vermont & St Agric College
Department
Type
DUNS #
066811191
City
Burlington
State
VT
Country
United States
Zip Code
05405
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Michalek, Arthur J; Kennedy, Guy G; Warshaw, David M et al. (2015) Flexural Stiffness of Myosin Va Subdomains as Measured from Tethered Particle Motion. J Biophys 2015:465693
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