MRI in mouse models of heart disease

小鼠心脏病模型中的 MRI

• 批准号: 9093799
• 负责人: Frederick H Epstein
• 金额: $ 34.58万
• 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 2017-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9093799
• 关键词: Acceleration; Activities of Daily Living; Advanced Glycosylation End Products; Adverse event; Animals; Biology; Blood Vessels; Blood flow; Cardiac; Cardiovascular system; Cells; Chronic; Complex; Coronary; Coronary Arteriosclerosis; Coronary heart disease; Diabetes Mellitus; Diabetic mouse; Diagnostic Factor; Disease; Environment; Enzymes; Epidemic; Evaluation; Exhibits; Functional disorder; Funding; Gadolinium; Gene Proteins; Gene-Modified; Goals; Gold; Health; Heart; Heart Diseases; Heart Rate; Human; Hyperglycemia; Image; Imaging Techniques; Individual; Infarction; Interobserver Variability; Intraobserver Variability; Kinetics; Lead; Left Ventricular Remodeling; Link; Magnetic Resonance Imaging; Measurement; Measures; Mediating; Methods; Microspheres; Microvascular Dysfunction; Modeling; Molecular; Morphologic artifacts; Motion; Mus; Myocardial; Myocardial Ischemia; Nature; Nitric Oxide Synthase Type I; Obesity; Organ; Organism; Patients; Physiological; Physiology; Prognostic Factor; Reproducibility; Resolution; Respiration; Rest; Role; Scanning; Secondary to; Spin Labels; Stress; Techniques; Testing; Time; Tissues; Tracer; Vascular Diseases; body system; contrast enhanced; diabetic; gadolinium oxide; gene product; imaging modality; improved; in vivo; macrovascular disease; mouse model; new therapeutic target; novel; prognostic; quantitative imaging; receptor; receptor for advanced glycation endproducts; research study; therapeutic target; tool; validation studies; vascular bed

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.

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估冠心病（CHD）至关重要。虽然随着 CHD 的进展，收缩功能会受损，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，是不良事件的预后，并且可能是其他冠状血管疾病的原因，例如在以下情况下：糖尿病伴高血糖。由于基因操作动物的现成性，小鼠模型被广泛用于研究先心病的分子机制。我们之前开发了电影 DENSE MRI 来量化小鼠的收缩功能，具有高精度、高分辨率且易于分析。我们还在基因修饰小鼠中应用多参数 MRI，以阐明各种受体和酶在正常心脏功能和梗死后左心室重塑中的作用。接下来，我们建议重点关注成像，通过评估小鼠的 MBF 来阐明冠状动脉微血管功能障碍的机制。我们和其他人之前已经证明了使用首过 MRI 和动脉自旋标记 (ASL) 的小鼠基本 MBF 成像，但是，通过使用压缩传感 (CS) 加速和改进的示踪动力学模型，我们建议对空间分辨率、扫描时间和定量。此外，我们建议进行比较研究，以确定哪种方法最准确且可重复。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），我们将检验晚期糖基化终末产物（AGE）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，我们将使用新颖的 CS 方法来开发 (a) 用于小鼠 MBF 成像的运动补偿双对比首过钆增强 MRI 技术，以及 (b) 用于在更少的时间内进行高分辨率 MBF 成像的加速 ASL MRI 技术。超过10分钟。在我们的第二个目标中，我们将使用微球作为金标准，比较和验证小鼠 MBF 成像的首过 MRI 和 ASL。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 和其他成像来测试 RAGE-/- 小鼠免受秋田小鼠发生的冠状微血管疾病的假设。这些目标的成功完成将导致量化小鼠 MBF 的成像方法得到改进。在一项特定应用中，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。