GLUT4 AND CARDIAC METABOLISM AND PHYSIOLOGY

描述(改编自申请人的摘要)：申请人陈述 胰岛素反应性葡萄糖转运体GLUT4的表达， 专门在心脏、骨骼肌和脂肪组织中发现的 在新陈代谢改变的状态下被下调，例如 糖尿病和肥胖症。根据申请人的说法，GLUT4基因缺失的小鼠 (不产生GLUT4的转基因小鼠)表现出修饰的葡萄糖 和脂肪代谢，并表现出显著的心肌肥厚 动脉血压升高。精确的机械控制 这种肥大的发展还不是很清楚。GLUT4为空 小鼠和GLUT4缺失小鼠与特异性转基因互补 仅在心脏(HO小鼠)中表达GLUT4的基因将用于 体内和体外实验研究改变底物的后果 心脏结构和功能的可用性。采用这些技术的实验 鼠标模型将回答以下问题：1.在 GLUT4基因缺失小鼠心脏肥大的结构和功能 发展，并将GLUT4放回HO小鼠的心脏使 葡萄糖摄取更正常会影响这种肥大的发展吗？在……里面 体外~(31)P核磁共振波谱和体内核磁共振氢谱 磁共振成像(MRI)将在不同的时间点用于 评估生物能量状态、心肌形态(质量、尺寸)和 功能(射血分数)。2.基板利用率是多少？ 在GLUT4缺失和HO心脏中与对照小鼠比较，并做 这些配置文件中的更改会影响功能吗？隔离灌流的心脏 GLUT4缺失和HO小鼠将被用来确定底物的变化 发展过程中不同时间点的利用和作用 肥大。3.GLUT4缺失小鼠肥大的心脏是如何 而HO小鼠的补充心脏对新陈代谢和 血流动力学压力？将使用几种方法来评估 缺乏GLUT4及其对心脏葡萄糖摄取的影响 GLUT4零和HO心脏承受应激条件的能力。

DESCRIPTION (adapted from the applicant's abstract): The applicant states that the expression of GLUT4, the insulin responsive glucose transporter, found specifically in the heart, skeletal muscle, and adipose tissue, has been shown to be down regulated in metabolically altered states such as diabetes and obesity. According to the applicant, GLUT4 null mice (genetically altered mice which do not make GLUT4) exhibit modified glucose and fat metabolism, and exhibit significant cardiac hypertrophy independent of increased arterial blood pressure. The precise mechanisms controlling the development of this hypertrophy are not well understood. The GLUT4 null mice and GLUT4 null mice complemented with a transgene specifically engineered to express GLUT4 in the heart only (HO mice) will be used in in vivo and in vitro experiments to study the consequences of altered substrate availability on cardiac structure and function. Experiments employing these mouse models will answer the following questions: 1. What changes occur in structure and function in the heart of GLUT4 null mice as hypertrophy develops, and does putting GLUT4 back into the heart of the HO mouse to make glucose uptake more normal affect the development of this hypertrophy? In vitro 31P nuclear magnetic resonance (NMR) spectroscopy and in vivo 1H magnetic resonance imaging (MRI) will be used at various time points to evaluate bioenergetic status, myocardial morphology (mass, dimensions) and function (ejection fraction). 2. What is the substrate utilization profile in the GLUT4 null and HO hearts as compared to control mice, and do alterations in these profiles affect function? Isolated perfused hearts of GLUT4 null and HO mice will be used to determine changes in substrate utilization and function at different time points in the development of hypertrophy. 3. How does the hypertrophic heart of the GLUT4 null mouse and the complemented heart of the HO mouse respond to metabolic and hemodynamic stress? Several methods will be used to assess what effect the lack of GLUT4 and its consequent effect on cardiac glucose uptake has on the ability of the GLUT4 null and HO heart to withstand stress conditions.