MRI in mouse models of heart disease

描述（由申请人提供）：心肌血流量（MBF）和收缩功能的测量是评估冠心病（CHD）的必要条件。虽然随着冠心病的进展，收缩功能受损会发生，但越来越多的人认为，伴有MBF储备受损的冠状动脉微血管疾病是冠心病的早期标志，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。由于转基因动物的现成可用性，小鼠模型被广泛用于研究冠心病的分子机制。我们之前开发了高密度磁共振成像（cine DENSE MRI），以高精度、高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功能和梗死后左心室重构中的作用。接下来，我们建议将重点放在影像学上，通过评估小鼠MBF来阐明冠状动脉微血管功能障碍的机制。我们和其他人已经证明了使用首过MRI和动脉自旋标记（ASL）对小鼠进行基本的MBF成像，然而，通过使用压缩感知（CS）和改进的示踪动力学建模加速，我们建议在空间分辨率、扫描时间和定量方面进行实质性的改进。此外，我们建议进行比较研究，以确定哪种方法最准确和可重复。随后，我们建议将MBF成像应用于高血糖糖尿病小鼠（秋田小鼠），在那里我们将验证晚期糖基化终产物（AGEs）和AGE受体（RAGE）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方法来开发(a)用于小鼠MBF成像的运动补偿双对比首次通过钆增强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，我们将比较和验证第一次通过MRI和ASL用于小鼠MBF成像，使用微球作为金标准。这一目标将包括可重复性研究。在我们的第三个目标中，我们将使用MBF和其他成像来验证RAGE-/-小鼠免受秋田小鼠发生的冠状动脉微血管疾病的假设。这些目标的成功完成将有助于改进小鼠MBF定量成像方法。在一个特定的应用中，MBF成像将用于确定RAGE在继发于糖尿病高血糖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.