CORE-- MODEL

核心——模型

• 批准号: 6808276
• 负责人: Michael R Zile
• 金额: $ 13.48万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6808276
• 关键词: biomedical facility; cats; disease /disorder model; heart enlargement; intracardiac pressure; laboratory mouse; model design /development; myocardial infarction; swine

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.

该计划项目的优势之一是我们有能力使人类疾病的困难和复杂动物模型，并通过对心室收缩压和舒张功能进行复杂的分析进行纵向跟随它们。这些分析还使我们能够研究负载条件变化的影响或损伤对心脏肥大和重塑的影响，后者构成了这些过程的血液动力学起始点。在一个试图定义肥大和重塑的原因和后果的程序项目中，最终有必要在完整动物中衡量体内原因和后果的影响，在分离的心脏组织中的体外和分离的心脏细胞体内体外。这些领域是我们以扎实的科学方式成功的领域。在制作临床相关的模型和生理测量时，我们利用了各种哺乳动物物种的优势。猪提出了一个大型动物模型，可以轻松地进行生理测量，心脏生理和冠状动脉解剖结构可与人相媲美，并且在先前实验的结果中有广泛的背景。猫的右心室提供了研究乳头状肌肉的研究，以检查经典的肌肉力学和 这些力学的病理状态。重要的是，对于这项工作，它还提供了压力或体积的源 - 肥大的右心室心细胞和组织，在这种情况下，我们在每种情况下都有相同的动物正常负载的对照左心室。尽管小鼠在制定相关模型和生理测量方面构成了巨大的挑战，但它为转基因操纵提供了令人兴奋的机会，以将因果关系和作用归因于各种遗传途径。我们已经成功地开发了制作临床相关模型，生理测量和涉及转基因小鼠系，腺病毒心脏细胞转染和小鼠完整左心室病毒感染的基因转移构建体的能力。此外，我们已经成功发展了制造体内和体外生理测量的能力，从中可以评估体积，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了管道，其中核心设施在基线和在肥大和重塑的过载或损伤过程中的各个时间点上准备模型并研究生理学。在终止体内研究时，现在已经表征了很好的动物心肌，现在已经 可用于肌肉生理，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学探索到比在体内更容易描绘机制的细胞的更简单性，然后是分子生物学领域更容易描绘的，在该领域中，基因特异性因素和基因的因果关系可以得到绘制。当前可用的动物模型是：具有心肌梗塞的猪；通过肺动脉带或右心室体积超负荷的右室压力超负荷的猫通过心房间隔术；左心室压力超负荷的小鼠通过横向主动脉束带和带心肌梗塞的小鼠。