CORE-- MODEL

该计划项目的优势之一是我们能够制作困难和复杂的人类疾病动物模型，并通过对心室收缩和舒张功能的复杂分析纵向跟踪它们。这些分析还使我们能够研究负荷条件变化的影响或损伤对心脏肥大和重塑的影响，这些影响形成了这些过程的血流动力学起始点。在一项旨在确定肥大和重塑的原因和后果的计划项目中，最终有必要在完整动物体内、离体心脏组织体外和离体心脏细胞体外测量原因和后果的影响。这些都是我们以坚实的科学方式取得成功的领域。在临床相关的模型和生理测量中，我们利用了各种哺乳动物物种的优势。猪是一种大型动物模型，其中可以容易地进行生理测量，心脏生理学和冠状动脉解剖学与人相当，并且其中存在先前实验结果的广泛背景。猫的右心室提供了乳头肌的研究，用于检查经典的肌肉力学和 病理状态的机制。对于这项工作重要的是，它还提供了压力或体积来源-肥大的右心室心肌细胞和组织，其中我们在每种情况下都有相同动物正常负荷的对照左心室。虽然小鼠在建立相关模型和生理测量方面提出了巨大的挑战，但它为转基因操作提供了令人兴奋的机会，特别是将因果关系归因于各种遗传途径。我们已经成功地开发了临床相关的模型，生理测量和基因转移结构，涉及转基因小鼠系，腺病毒心肌细胞转染和病毒感染的小鼠完整的左心室的能力。此外，我们还成功开发了进行体内和体外生理测量的能力，可以评估体积、质量、几何形状、收缩和舒张功能的变化。典型的动物模型形成一个管道，其中核心机构准备模型并在基线和过载或损伤进展至肥大和重塑期间的不同时间点研究生理学。在体内研究结束时，已经在生理学上充分表征的动物的心肌， 可用于肌肉生理学、细胞生物学和分子生物学研究。结果是，从动物模型核心开始，科学从完整的体内生理探索发展到细胞的更简单性，其中机制比体内更容易描绘，然后发展到分子生物学领域，其中可以绘制基因特异性因果关系。目前可用的动物模型有：猪心肌梗死模型;猫肺动脉结扎右心室压力超负荷模型或房间隔切开右心室容量超负荷模型;小鼠横主动脉结扎左心室压力超负荷模型和心肌梗死模型。

One of the strengths of this Program Project is our ability to make difficult and complex animal models of human disease, and to follow them longitudinally with sophisticated analysis of ventricular systolic and diastolic function. These analyses have also allowed us to study the effects of changes in loading conditions or the effects of injury on cardiac hypertrophy and remodeling which form the hemodynamic initiation point of these processes. In a Program Project, which seeks to define the causes and consequences of hypertrophy and remodeling, it is eventually necessary to measure the effects of both the causes and consequences in vivo in the intact animal, in vitro in isolated cardiac tissue and in vitro in isolated cardiocytes. These are areas where we have succeeded in a solid scientific fashion. In making clinically relevant models and physiologic measurements, we have exploited the advantages of various mammalian species. The pig presents a large animal model in which physiological measurements can readily be made, cardiac physiology and coronary anatomy is comparable to man, and in which there is a wide background of the results of previous experiments. The right ventricle of the cat offers study of papillary muscles for examination of classic muscle mechanics and the effect of pathologic states on those mechanics. Importantly for this work, it also provides a source of pressure or volume - hypertrophied right ventricular cardiocytes and tissue wherein we have in each case, a same-animal normally loaded control left ventricle. While the mouse poses formidable challenges in making relevant models and physiologic measurements, it offers the exciting opportunity for transgenic manipulation in specifically ascribing cause and effect to various genetic pathways. We have successfully developed the ability to make clinically relevant models, physiologic measurements, and gene transfer constructs involving transgenic mouse lines, adenoviral cardiocyte transfections and viral infections of intact left ventricle in mice. In addition, we have successfully developed the ability to make in vivo and in vitro physiologic measurements, from which changes in volume, mass, geometry, systolic and diastolic function can be assessed. A typical animal model forms a pipeline in which the Core Facility prepares the model and studies physiology at baseline and at various time points during the progression of the overload or injury to hypertrophy and remodeling. At the termination of the in vivo studies, the myocardium of an animal, which has been well characterized physiologically, is now available for muscle physiology, cell biological and molecular biological investigation. The result is that starting with the Animal Model Core there is a progression of science from intact in vivo physiologic exploration to the greater simplicity of the cell where mechanisms are more easily delineated than they are in vivo and then to the realm of molecular biology where gene-specific cause and effect relationships may be drawn. The animal models currently available are: the pig with myocardial infarction; the cat with right ventricular pressure overload via pulmonary artery banding or right ventricular volume overload via atrial septotomy; the mouse with left ventricular pressure overload via transverse aortic banding, and mouse with myocardial infarction.