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: 8374705
• 负责人: BRADLEY M PALMER
• 金额: $ 49.29万
• 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/8374705
• 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集成核心（核心 B）将用于表征和集成 MyBP-C 磷酸化和肌动蛋白结合对工作小鼠左心室 (LV) 和化学皮肤心脏纤维的机械后果：体内小鼠 LV 的表型特征将由 Drs 进行。约翰·霍普金斯大学的 Kass 和 Takimoto 使用小型化容积电导导管系统来记录接近生理条件下的左心室压力-容积环。这些测量将产生小鼠左心室收缩和舒张功能的各种复杂参数，这些参数与人类的类似参数相关。心肌丝的体外表型特征将由 Drs 进行评估。佛蒙特大学的 Palmer 和 Maughan 在化学剥皮心肌纤维制备中使用了多种机械测定法。左心室和心肌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 中提出的具体假设。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 末端 与肌动蛋白相互作用，可以影响细丝激活和/或对肌节施加机械负荷，并且 (iii) MyBP-C 磷酸化和/或肌动蛋白相互作用改变肌动球蛋白动力学，例如肌球蛋白时间开启。 Core 中在肌丝水平上进行的多项测量（包括肌球蛋白时间开启）预计将与 Project #2-Warshaw/VanBuren 在单分子水平上进行的测量直接相关。该核心的集成部分将证明在分子水平上发现的机械测量与心脏纤维和工作左心室的肌丝晶格的几何形状的相关性。然后，将对该核心进行的研究进行协调和比较，旨在系统地将分子水平的发现（项目#2-Warshaw/VanBuren）与肌丝和肌纤维机械性能的测量结果相结合。 心室水平（项目#3-Robbins）。