Core--Mouse physiology

核心--小鼠生理学

• 批准号: 6564935
• 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: 2002
• 资助国家: 美国
• 起止时间: 2002-02-01 至 2003-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6564935
• 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基因靶向去除候选基因，为研究肥厚和心力衰竭的细胞机制提供了重要的见解。虽然收缩能力是使用分层方法来评估的，该方法检查组成心肌细胞、分离的肌纤维和分离的心脏的力学机制，但该SCOR的一个基本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。在这一点上，心脏的特征是一个连接全身和静脉循环的肌肉泵；对综合心血管功能的分析包括补偿分子、几何血管和神经体液机制，这些机制产生特定基因修饰的最终表型结果。因此，老鼠生理学核心的目标是：1)执行连续的、非侵入性的修改。因此，小鼠生理学核心的目标是：1)利用超声心动图对心血管表型进行连续、非侵入性的“筛选”(即初步表征)，以检测遗传和生理改变小鼠的突变和病理变化；2)使用非侵入性(超声心动图)和有创性(导管术)方法，全面表征心血管表型变化，包括左心室重构、左心室重量以及收缩和舒张期功能；3)在遗传和生理改变的动物中定位异常的细胞内钙处理并使用力-间隔行为参数(力-频率关系、机械和松弛恢复、早搏后增强以及对ryanodine的反应)在体内评估兴奋-收缩偶联；以及4)造成可叠加在基因改变的动物身上的急性(容量负荷、药理学挑战)和慢性病理生理扰动(横主动脉环扎、主动脉腔瘘)。使用这些方法，可以评估心肌细胞的内在特性、纤维力学、细胞外基质、腔室特性、负荷条件以及神经激素代偿机制对它们的调节之间的相互作用，以了解特定蛋白质的功能作用、其丰度及其在体内的异构体。