Hyperpolarized 13C imaging for studying beta-oxidative and anaplerotic pathways

描述（由申请人提供）：使用13C标记底物，快速溶解动态核极化（fd- DNP）和磁共振成像（MRI）测量体内通量是最有前途的体内分子成像新技术之一。到目前为止，几乎所有关于DNP的研究都集中在使用[1-13C]丙酮酸盐作为成像底物。虽然最初的结果已经证明了该方法的巨大潜力，但丙酮酸的固有局限性是它只能探测有限数量的途径。将该方法扩展到研究其他途径，如b-氧化或回溶，将大大扩大其应用范围。我们的研究对象是来自C57BL/6J （B6）小鼠的灌注心脏（对照）和压力过载的主动脉带模型。我们假设LVH会导致注射[1-13C]丙酮酸后[13C]碳酸氢盐产量增加，而丙酸刺激会进一步增加可观察到的HP碳酸氢盐的量。这些假设将在灌注的小鼠心脏中使用HyperSense DNP偏振器和定制的10毫米，13c优化的冷冻探针进行测试。与使用这套设备的标准同位素分析相比，灵敏度的提高将达到10万至14万倍。左心室肥厚是一种与糖尿病和肥胖相关的常见疾病。LVH在一般情况下可发展为心力衰竭（HF），这是美国和发达国家常见的死亡原因。LVH通常与心肌能量变化有关，与正常底物脂肪酸相比，心脏被认为优先氧化葡萄糖。分子成像技术的发展可以检测体内能量学变化的开始，或者可能监测新兴的“代谢疗法”的效果，这将是医疗保健领域的一项重大发展。本建议的重点是确定心肌基质偏好的可靠生物标志物。我们假设[13C]碳酸氢盐可以在注射超极化[1- 13C]丙酮酸后作为这样的标记物。

DESCRIPTION (provided by applicant): Measurement of in vivo flux using 13C labeled substrates, fast dissolution dynamic nuclear polarization (fd- DNP), and magnetic resonance imaging (MRI) is one of the most promising new technologies for molecular imaging in vivo. Almost all research in DNP to this point has focused on the use of [1-13C]pyruvate as the imaging substrate. While initial results have demonstrated the fantastic potential of the methodology, the inherent limitation of pyruvate is that it probes a limited number of pathways. Extension of the methodology to study other pathways such as b-oxidation or anaplerosis would dramatically expand the scope of its utilization. Our target of study is the perfused heart from the C57BL/6J (B6) mouse (control) and an aortic band model of pressure overload. We hypothesize that LVH will lead to increased [13C]bicarbonate production following injection of [1-13C]pyruvate, and that a propionate challenge will further increase the amount of HP bicarbonate that is observable. These hypotheses will be tested in the perfused mouse heart using a HyperSense DNP polarizer and a custom built 10 mm, 13C-optimized cryoprobe. The increase in sensitivity over standard isotopomer analysis using this suite of equipment will be on the order of 100000 to 140000 times. Relevance Left ventricular hypertrophy is a common malady associated with diabetes and obesity. LVH can under common circumstances progress to heart failure (HF), a common cause of mortality in the US and developed world. LVH is commonly associated with a change in myocardial energetics, where the heart is thought to preferentially oxidize glucose as compared to its normal substrate of choice, fatty acids. Development of a molecular imaging technique that could detect the onset of changes in energetics in vivo or possibly monitor the effects of the emerging "metabolic therapies" would constitute a major development in healthcare. This proposal is focused on identifying a reliable biomarker of substrate preference in the myocardium. We hypothesize that [13C]bicarbonate could serve as such a marker following injection of hyperpolarized [1- 13C]pyruvate.