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）：过去 10 年中，利用转基因和基因敲除小鼠进行的实验显着推进了心血管疾病研究的广泛领域。绝大多数此类研究都采用离体方法来评估基因操作（表型）的结果，例如免疫染色组织样本，并且对于心脏功能，在孤立的 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 方法来对小鼠心肌梗死 (MI) 和局部心肌内功能进行成像，并将这些方法应用于 MI 后左室功能障碍的研究。具体来说，我们将使用新型位移编码 MRI 技术来研究急性和慢性 MI 情况下的心肌功能障碍，重点研究源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，因为心肌梗死后左心室功能障碍和重构是美国死亡的主要原因。了解左心室功能障碍和重塑的基本机制可能有助于药物开发和改进治疗。因此，我们的具体目标是 1. 开发用于 MI 后小鼠心脏成像的新型 MRI 方法，该方法可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，并同时将心肌梗塞区域描绘为对比增强幅度重建图像中的超增强区域。 2. 开发图像分析技术来自动分割心肌，检测延迟超增强区域，并计算梗塞、邻近和远端区域的心肌功能测量值。 3.使用MRI，包括目标1和2中开发的方法，使用敲除小鼠和直接基因转移方法阐明一氧化氮(NO)和诱导形式一氧化氮合酶(iNOS)对ML后LV功能障碍的作用。