Ventricular and Cardiac Fiber Characterization and Integration Core

心室和心脏纤维表征和集成核心

• 批准号: 8432074
• 负责人: BRADLEY M PALMER
• 金额: $ 48.04万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8432074
• 关键词: Actins; Adrenergic Agents; Affect; Area; Binding; Binding Sites; Biological Assay; Cardiac; Cardiac Myosins; Catheters; Characteristics; Cyclic AMP-Dependent Protein Kinases; Data; Fiber; Heart; Human; In Vitro; Investigation; Kinetics; Left; Left ventricular structure; Measurement; Measures; Mechanics; Microfilaments; Molecular; Molecular Motors; Mus; Mutation; Myocardial; Myocardium; Myosin ATPase; Organ; Performance; Phosphorylation; Phosphorylation Site; Physiological; Preparation; Production; Protein Dephosphorylation; Regulation; Role; Sarcomeres; Serine; Services; Site; Skin; Structure; System; Takeda brand of pioglitazone hydrochloride; Testing; Thin Filament; Time; Universities; Ventricular; Vermont; Work; adrenergic; in vivo; indexing; miniaturize; myosin-binding protein C; pressure; single molecule

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).

心室和心脏纤维表征和整合核心（Core B）将用于表征和整合MyBP-C磷酸化和肌动蛋白结合对工作小鼠左心室（LV）和化学剥皮的心脏纤维的机械后果。约翰霍普金斯大学的Kass和Takimoto使用一种小型化的体积传导导管系统来记录接近生理条件下的左室压力-容积回路。这些测量将导致小鼠左室收缩和舒张功能的各种复杂参数，这些参数与人类的相似参数相关。心脏肌丝的体外表型特征将由博士评估。佛蒙特大学的Palmer和Maughan在化学剥皮的心脏纤维制备中使用了各种机械分析。在左室和心脏纤维中进行的测量将提供数据，直接测试项目#2-Warshaw/VanBuren和#3-Robbins中提出的特定假设。这些假设是：(i) MyBP-C磷酸化的机械后果需要特定位点和/或位点序列的磷酸化，（ii） MyBP-C的n端