MRI in mouse models of heart disease

描述（由申请人提供）：心肌血流量（MBF）和收缩功能的测量对于评价冠心病（CHD）至关重要。虽然随着CHD的进展，收缩功能受损，但越来越多的观点认为，MBF储备受损的冠状动脉微血管疾病是CHD的早期标志物，是不良事件的预后，并且可能导致其他冠状动脉血管疾病，例如糖尿病伴高血糖症。由于基因操作动物的现成可用性，小鼠模型被广泛用于研究CHD的分子机制。我们之前开发了电影DENSE MRI，以高准确度，分辨率和易于分析的方式量化小鼠的收缩功能。我们还在基因修饰小鼠中应用多参数MRI来阐明各种受体和酶在正常心脏功能和梗死后左心室重构中的作用。接下来，我们建议集中在成像，以阐明机制的冠状动脉微血管功能障碍的评估MBF在小鼠。我们和其他人以前已经证明了使用首过MRI和动脉自旋标记（ASL）在小鼠中进行基本MBF成像，但是，通过使用压缩传感（CS）和改进的示踪剂动力学建模进行加速，我们建议对空间分辨率、扫描时间和定量进行实质性改进。此外，我们建议进行比较研究，以确定哪种方法是最准确和重现性。随后，我们建议在高血糖糖尿病小鼠（秋田小鼠）中应用MBF成像，在那里我们将测试晚期糖基化终末产物（AGEs）和AGE受体（AGEs）介导高血糖冠状动脉微血管功能障碍的假设。为了实现这些目标，我们有三个具体目标。首先，我们将使用新的CS方法开发（a）用于小鼠MBF成像的运动补偿双对比度首过钆增强MRI技术和（B）用于在不到10分钟内进行高分辨率MBF成像的加速ASL MRI技术。在我们的第二个目标中，我们将使用微球作为金标准，比较和验证用于小鼠MBF成像的首过MRI和ASL。这一目标将包括再现性研究。在我们的第三个目标中，我们将使用MBF和其他成像来测试以下假设：AZ-/-小鼠免受秋田小鼠中发生的冠状动脉微血管疾病的影响。这些目标的成功完成将导致改进的成像方法定量小鼠MBF。在一个特定的应用中，MBF成像将被用于建立糖尿病高血糖继发的冠状动脉微血管疾病中的作用。

DESCRIPTION (provided by applicant): Measurements of myocardial blood flow (MBF) and contractile function are essential to the evaluation of coronary heart disease (CHD). While compromised contractile function occurs as CHD advances, a growing concept is that coronary microvascular disease with impaired MBF reserve is an early marker of CHD, is prognostic of adverse events, and is potentially causal of additional coronary vascular disease, such as in the setting of diabetes with hyperglycemia. Due to the ready availability of genetically-manipulated animals, mouse models are widely used to investigate molecular mechanisms underlying CHD. We previously developed cine DENSE MRI to quantify contractile function in mice with high accuracy, resolution, and ease of analysis. We also applied multi-parametric MRI in gene-modified mice to elucidate the roles of various receptors and enzymes in normal cardiac function and in post-infarct left-ventricular remodeling. Next, we propose to focus on imaging to elucidate mechanisms underlying coronary microvascular dysfunction by assessment of MBF in mice. Basic MBF imaging in mice using first-pass MRI and arterial spin labeling (ASL) have previously been demonstrated by us and others, however, through acceleration using compressed sensing (CS) and improved tracer kinetic modeling, we propose to develop substantial improvements to spatial resolution, scan time, and quantitation. Furthermore, we propose comparison studies to determine which method is most accurate and reproducible. Subsequently, we propose to apply MBF imaging in hyperglycemic diabetic mice (Akita mice), where we will test the hypothesis that advanced glycation end products (AGEs) and the receptor for AGE (RAGE) mediate hyperglycemic coronary microvascular dysfunction. To accomplish these goals we have three specific aims. First, we will use novel CS methods to develop (a) a motion-compensated dual-contrast first- pass gadolinium-enhanced MRI technique for MBF imaging in mice and (b) an accelerated ASL MRI technique for high-resolution MBF imaging in less than 10 minutes. In our second aim we will compare and validate first- pass MRI and ASL for MBF imaging in mice, using microspheres as a gold standard. This aim will include reproducibility studies. In our third aim we will use MBF and other imaging to test the hypothesis that RAGE-/- mice are protected from coronary microvascular disease that develops in akita mice. The successful completion of these aims would lead to improved imaging methods for quantifying MBF in mice. In one particular application, MBF imaging would be used to establish the role of RAGE in coronary microvascular disease secondary to diabetic hyperglycemia.