MRI of Myocardial Function in Post-Infarct Knockout Mice

梗塞后基因敲除小鼠心肌功能的 MRI

• 批准号: 6929930
• 负责人: Frederick H Epstein
• 金额: $ 33.42万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-05 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6929930
• 关键词: bioimaging /biomedical imaging; cardiovascular imaging /visualization; electrocardiography; gene targeting; genetically modified animals; heart function; heart ventricle; immunocytochemistry; laboratory mouse; magnetic resonance imaging; method development; muscle function; myocardial infarction; nitric oxide synthase

DESCRIPTION (provided by applicant): Over the past 10 years experiments utilizing transgenic and knockout mice have significantly advanced broad areas of cardiovascular disease research. The vast majority of such research has employed ex vivo methods for assessing the results of gene manipulation (phenotyping) such as immunostaining tissue samples, and, for heart function, performing catheter-based measurements of left-ventricular (LV) pressure in isolated Langendorff-perfused hearts. For studies of cardiac function in particular, noninvasive imaging offers the possibility of making measurements that directly reflect complex in vivo physiology. Basic echocardiographic and MRI techniques have already been developed and applied to mice, and MRI in particular, due to its versatility and accuracy, shows great promise. We propose to develop advanced MRI methods for imaging myocardial infarction (MI) and regional intramyocardial function in mice and to apply these methods to the study of LV dysfunction after MI. Specifically, we will use novel displacement-encoded MRI techniques to study myocardial dysfunction in the settings of acute and chronic MI, focusing on the role of excess nitric oxide (NO) derived from the inducible form of nitric oxide synthase (iNOS). While these studies focus on basic mechanisms, they are clinically relevant because post-MI LV dysfunction and remodeling are a major cause of mortality in the United States. Understanding the basic mechanisms underlying LV dysfunction and remodeling may lead to drug development and improved treatment. Accordingly, our specific aims are 1. To develop novel MRI methods for post-MI mouse heart imaging that measure two-dimensional (2D) and 3D intramyocardial tissue displacement and strain in phase-reconstructed images and simultaneously depict the area of myocardial infarction as a region of hyper enhancement in contrast-enhanced magnitude-reconstructed images. 2. To develop image analysis techniques to automatically segment the myocardium, detect the area of delayed hyper enhancement, and compute measures of myocardial function localized to the infarcted, adjacent, and remote regions. 3. To use MRI, including the methods developed in Aims 1 and 2, to elucidate the roles of nitric oxide (NO) and the inducible form of nitric oxide synthase (iNOS) on post-Ml LV dysfunction using knockout mice and direct gene transfer methods.

描述（由申请人提供）：在过去的10年中，利用转基因和基因敲除小鼠的实验显著推进了心血管疾病研究的广泛领域。绝大多数此类研究采用了离体方法来评估基因操作（表型分析）的结果，如免疫染色组织样本，以及心脏功能，在离体Langendorff灌注心脏中进行基于导管的左心室（LV）压力测量。特别是对于心脏功能的研究，无创成像提供了直接反映复杂的体内生理学的测量的可能性。基本的超声心动图和MRI技术已经开发出来并应用于小鼠，特别是MRI，由于其多功能性和准确性，显示出巨大的前景。我们建议开发先进的MRI方法成像心肌梗死（MI）和局部心肌内功能的小鼠，并将这些方法应用于MI后左室功能障碍的研究。具体来说，我们将使用新的位移编码MRI技术来研究急性和慢性MI的心肌功能障碍，重点是来自诱导型一氧化氮合酶（iNOS）的过量一氧化氮（NO）的作用。虽然这些研究侧重于基本机制，但它们具有临床相关性，因为MI后LV功能障碍和重塑是美国死亡率的主要原因。了解LV功能障碍和重塑的基本机制可能会导致药物开发和改善治疗。因此，我们的具体目标是1。开发MI后小鼠心脏成像的新型MRI方法，测量相位重建图像中的二维（2D）和3D心肌内组织位移和应变，同时将心肌梗死区域描绘为对比度增强幅度重建图像中的高增强区域。2.开发图像分析技术，以自动分割心肌，检测延迟性高增强区域，并计算梗死、邻近和远端区域的心肌功能指标。3.使用MRI，包括目的1和2中开发的方法，使用基因敲除小鼠和直接基因转移方法阐明一氧化氮（NO）和诱导型一氧化氮合酶（iNOS）对MI后LV功能障碍的作用。