IN VIVO MURINE CARDIAC ENERGY METABOLISM AND FUNCTION

高能磷酸盐（HEP）代谢为正常心脏提供能量 收缩功能，并对肌细胞活力至关重要。虽然 令人兴奋的心血管病理学转基因小鼠模型， 但是，以前不可能无创地评估两者 心脏能量代谢和收缩力或其调节下 生理条件，由于心脏尺寸小（心脏重量 70-200 mg）和高心率（~ 600/min）。我们在这里描述第一个 研究证明了联合非侵入性 高分辨率磁共振（MR）图像引导心脏31 P波谱I 小鼠该提案旨在进一步优化这些MR成像和光谱学 技术，以提供一个强大的，可靠的非侵入性检查， 研究野生型和非野生型的体内心脏能量代谢和功能， 转基因小鼠的生理心率。我们还建议使用这些 结合技术来评估两个最近描述的转基因模型， 高血压和正常血压肥大。具体目标是：目标1： 优化组合的31 P MR光谱和1H MR成像方法， 确定心脏HEP和功能的正常年龄相关范围， 目的2：开发和实施一种在生理条件下的体内 负荷试验评估小鼠心脏代谢和收缩储备，目的 3：检验以下假设： GLUT 4转运蛋白的消融导致心肌细胞凋亡的反常增加， PCr/ATP比值，并检验解释潜在机制的两个假设 考虑到这一已证实的观察结果，目标4：检验假设， 高血压肥大伴ATP利用增加，由 内皮源性一氧化氮（eNOS）基因的消融（与 正常血压的GLUT 4肥大无效），随着时间的推移， 能量储备和收缩功能障碍。这是第一个非侵入性的工具， 研究心脏结构，收缩功能和生物能量学， 一次检查中的生理状况对于心血管疾病的诊断是非常宝贵的。 希望研究转基因生物的生理学意义的研究人员 在小鼠中的操作。它还能让我们测试特定的代谢 两种不同的肥大模型的假设。

High-energy phosphate (HEP) metabolism fuels normal cardiac contractile function and is essential for myocellular viability. Although exciting transgenic murine models of cardiovascular pathology are now available, it has not been previously possible to noninvasively assess both cardiac energy metabolism and contractility or their regulation under physiologic conditions, due to the small cardiac dimensions (heart weights 70-200 mg) and high heart rates (-600/min) of mice. We describe here the first studies demonstrating the feasibility of doing combined non-invasive high-resolution magnetic resonance (MR) image-guided cardiac 31P spectroscopy I mice. This proposal aims to further optimize these MR imaging and spectroscopy techniques in order to provide a robust, reliable non-invasive exam for studying in vivo cardiac energy metabolism and function in wild-type and transgenic mice at physiologic heart rates. We also propose using these combined techniques to evaluate two recently described transgenic models of hypertenisve and normotensive hypertrophy. The specific aims are: Aim 1: To optimize combined 31P MR Spectroscopic and 1H MR imaging methods and to determine the normal age-associated ranges of cardiac HEP's and function in mice under physiologic conditions, Aim 2: To develop and implement an in vivo stress test for assessing murine cardiac metabolic and contractile reserve, Aim 3: To test the hypothesis that the primary metabolic abnormality resulting from ablation of the GLUT4 translocator results in a paradoxical increase in cardiac PCr/ATP ratio, and to test two hypotheses explaining potential mechanisms accounting for this confirmed observation, Aim 4: To test the hypothesis that hypertensive hypertrophy with increased ATP utilization, resulting from ablation of the endothelial-derived nitric oxide (eNOS) gene (in contrast to the normotensive hypertrophy of GLUT4 nulls), over time develops decreased energy reserve and contractile dysfunction. This first non-invasive tool for studying cardiac structure, contractile function, and bioenergetics under physiologic conditions in a single exam will be invaluable for cardiovascular investigators wishing to study the physiologic significance of transgenic manipulations in mice. It will also allow us to test specific metabolic hypotheses in two distinct hypertrophic models.