Core--Mouse physiology

SCOR项目中使用转基因过表达和基因靶向消融候选基因的功能获得和功能丧失策略为肥厚和心力衰竭背后的细胞机制提供了重要的见解。尽管收缩性是通过分层方法来评估的，该方法检查了组成肌细胞、分离的肌纤维和分离的心脏的力学，但这种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进行严格检查。在这方面，心脏的特点是与全身循环和静脉循环耦合的肌肉泵；综合心血管表现的分析包括代偿性分子、几何血管和神经体液机制，这些机制作用于产生特定基因修饰的最终表型后果。因此，小鼠生理学核心的目标是：1)进行串行的、非侵入性的修饰。因此，小鼠生理学核心的目标是：1)用超声心动图对心血管表型进行一系列非侵入性“筛查”（即初始表征），以检测基因和生理改变小鼠的突变和病理变化；2)利用无创（超声心动图）和有创（置管）方法，充分表征心血管表型变化，包括左室重塑、左室肿块、收缩和舒张功能；3)在基因和生理改变的动物中，利用力-间隔行为参数（力-频率关系、机械和松弛恢复、收缩后增强和对瑞诺定的反应）来定位细胞内异常钙处理和评估体内兴奋-收缩耦合；4)制造急性（容量负荷、药理学挑战）和慢性病理生理扰动（主动脉横带、主动脉腔瘘），这些干扰可以叠加在转基因动物身上。利用这些方法，可以评估心肌细胞内在特性、纤维力学、细胞外基质、腔室特性、负载条件以及它们在神经激素代偿机制下的调节之间的相互作用，从而了解特定蛋白质的功能作用、其丰度及其在体内的异构体。

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.