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

描述(申请人提供)：使用13C标记底物测量体内通量、快速溶解动态核极化(FD-DNP)和磁共振成像(MRI)是最有前途的体内分子成像新技术之一。到目前为止，几乎所有的DNP研究都集中在使用[1-13C]丙酮酸作为成像底物。虽然初步结果已经证明了该方法的神奇潜力，但丙酮酸的固有局限性是它只能探索有限数量的途径。将方法论扩展到研究其他途径，如b-氧化或反转作用，将极大地扩大其使用范围。我们的研究对象是C57BL/6J(B6)小鼠(对照)的灌流心脏和压力超负荷的主动脉带模型。我们假设，在注射[1-13C]丙酮酸后，LVH将导致[13C]碳酸氢盐产量增加，丙酸挑战将进一步增加可观察到的HP碳酸氢盐的量。这些假设将在灌流的小鼠心脏中使用HyperSense DNP偏振器和定制的10 mm、13C优化的冷冻探头进行测试。与使用这套设备的标准同位素分析相比，灵敏度将提高约100000至140000倍。左心室肥厚是糖尿病和肥胖症的常见疾病。在普通情况下，左心室肥厚可发展为心力衰竭(HF)，这是美国和发达国家的一种常见死亡原因。LVH通常与心肌能量学改变有关，在这种情况下，心脏被认为优先氧化葡萄糖，而不是它选择的正常底物脂肪酸。开发一种分子成像技术，可以检测体内能量变化的开始，或者可能监测新兴的“代谢疗法”的效果，将构成医疗保健领域的一项重大发展。这项建议的重点是确定一个可靠的生物标记物的底物偏好在心肌。我们假设在注射超极化的[1-13C]丙酮酸后，[13C]碳酸氢盐可以作为这样的标记物。

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.