GLUT4 AND CARDIAC METABOLISM AND PHYSIOLOGY

描述（改编自申请人摘要）：申请人声明 GLUT4的表达，胰岛素反应性葡萄糖转运蛋白， 特别是在心脏、骨骼肌和脂肪组织中发现的， 在代谢改变的状态下， 糖尿病和肥胖症。 根据申请方，GLUT 4缺失小鼠 （不产生GLUT 4的基因改变小鼠）表现出修饰的葡萄糖 和脂肪代谢，并表现出显着的心脏肥大独立 动脉血压升高 精确的控制机制 这种肥大的发展尚不清楚。 GLUT4 null 小鼠和GLUT4缺失小鼠， 仅在心脏中表达GLUT4的基因工程小鼠（HO小鼠）将用于 体内和体外实验，以研究改变底物的后果 心脏结构和功能的可用性。 实验采用这些 小鼠模型将回答以下问题：1。 如何变幻 GLUT4基因敲除小鼠心脏的结构和功能， 开发，并将GLUT 4放回HO小鼠的心脏， 葡萄糖摄取正常多会影响这种肥大的发展吗？ 在 体外31P核磁共振（NMR）光谱和体内1H 将在不同时间点使用磁共振成像（MRI）， 评估生物能量状态、心肌形态（质量、尺寸）和 射血分数（ejection fraction） 2. 什么是基板利用率概况 与对照小鼠相比，在GLUT4缺失和HO心脏中， 这些特征的改变会影响功能吗？ 离体灌流心脏 GLUT4 null和HO小鼠将用于确定底物的变化 在发展过程中不同时间点的利用和作用 肥厚 3. GLUT4基因敲除小鼠的肥大心脏 HO小鼠的补充心脏对代谢和 血流动力学应激？ 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， GLUT 4无效和HO心脏耐受应激条件的能力。

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.