Core--Mouse physiology

核心--小鼠生理学

• 批准号: 6317576
• 负责人: BRIAN D HOIT
• 金额: $ 24.41万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-02-14 至 2005-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6317576
• 关键词: animal colony; biomedical facility; calcium flux; cardiovascular function; catheterization; echocardiography; genetically modified animals; genotype; heart surgery; laboratory mouse; phenotype

The gain and loss of function strategies employed in the SCOR projects using transgenic over-expression and gene-targeted ablation of candidate genes have provide important insights into the cellular mechanisms that underlie hypertrophy and heart failure. Whereas contractility is assessed using a hierarchical approach that examines the mechanics of constituent myocytes, isolated myofibers, and the isolated heart, an essential component of this SCoR is the critical examination of cardiovascular physiology in the intact animal under various physiologic and pathologic conditions. In this regard, the heart is characterized as a muscular pump coupled to the systemic and venous circulations; analysis of integrated cardiovascular performance incorporates the compensatory molecular, geometric vascular and neurohumoral mechanisms that act to produce the ultimate phenotypic consequences of a specific genetic modification. Accordingly, the goals of the Mouse Physiology Core are: 1) To perform serial, non-invasive modification. Accordingly, the goals of the Mouse Physiology Core are: 1) To perform serial, non-invasive "screening" (i.e. an initial characterization) of cardiovascular phenotypes with echocardiography in order to detect mutational and pathological changes in genetically and physiologically altered mice; 2) To fully characterize cardiovascular phenotype changes, including LV remodeling, LV mass, and systolic and diastolic functions, using non-invasive (echocardiography) and invasive (catheterization) methods; 3) To localize abnormal intracellular calcium handling and assess excitation-contraction coupling in vivo using parameters of force-interval behavior (force- frequency relation, mechanical and relaxation restitution, post- extrasystolic potentiation, and the response to ryanodine) in genetically and physiologically altered animals; and 4) To create acute (volume loading, pharmacological challenges) and chronic pathophysiological perturbations (transverse aortic banding, aortocaval fistula) that can be superimposed on genetically altered animals. Using these methods, the interplay among the intrinsic properties of cardiomyocytes, fiber mechanics, extracellular matrix, chamber properties, loading conditions, and their modulation by neurohormonal compensatory mechanisms, can be assessed to understand the functional role of a specific protein, its abundance, and its isoform in the in vivo context.

在SCOR项目中采用的功能获得和丧失策略，使用转基因过表达和候选基因的基因靶向消融，为肥大和心力衰竭的细胞机制提供了重要的见解。收缩性是使用分层方法评估的，该方法检查了组成肌细胞、分离肌纤维和分离心脏的力学，该SCoR的一个重要组成部分是在各种生理和病理条件下对完整动物的心血管生理学进行关键检查。在这方面，心脏的特点是作为一个肌肉泵耦合到全身和静脉循环;综合心血管性能的分析纳入了代偿分子，几何血管和神经体液机制，其作用是产生最终的表型后果的特定的遗传修饰。因此，小鼠生理学核心的目标是：1）进行连续的，非侵入性的修改。因此，小鼠生理学核心的目标是：1）进行系列的，非侵入性的“筛选”使用超声心动图对心血管表型进行（即初始表征），以检测遗传和生理改变小鼠的突变和病理变化; 2）为了充分表征心血管表型变化，包括LV重构、LV质量以及收缩和舒张功能，使用非侵入性（超声心动图）和侵入性（导管插入）方法; 3）使用力-间期行为参数定位异常的细胞内钙处理并评估体内兴奋-收缩偶联（力-频率关系、机械和松弛恢复、期前收缩后增强和对ryanodine的反应）;和4）产生急性（容量负荷、药理学挑战）和慢性病理生理学扰动（横向主动脉束带、下腔静脉瘘），其可叠加在遗传改变的动物上。使用这些方法，心肌细胞，纤维力学，细胞外基质，腔室特性，负荷条件和它们的神经激素补偿机制的调制的内在属性之间的相互作用，可以进行评估，以了解特定蛋白质的功能作用，它的丰度，和它的异构体在体内的情况下。