Hyperpolarized 13C MRI of renal mitochondrial dysfunction

项目摘要 线粒体功能障碍被认为是糖尿病肾病疾病进展的关键早期驱动因素 (DN)，在其他慢性疾病中，但用于线粒体非侵入性评估的工具很少。 status.鉴于DN是糖尿病相关发病率和死亡率的重要来源（通过其对糖尿病的影响）， 心血管结局），更好地理解甚至潜在地预测患者进展的能力 糖尿病合并DN可能对糖尿病的临床管理产生很大影响。R21的目的 提案（“肾脏、泌尿系统和血液系统疾病的催化工具和技术开发”）的目的是 开发具有超极化（HP）13 C MRI的ESTA特异性反应性的新成像探针，[1，3- 13 C2]乙酰乙酸（AcAc），提供线粒体代谢状态的非侵入性读出。线粒体- 相对于HP 13 C技术，靶向酮体探针具有几个有利的特征，包括长T1 信号寿命、低毒性和快速细胞摄取，但也具有主要的相关挑战， 阻碍了发展。为了解决这些问题，我们提出了几项技术创新，包括：1）改进 化学合成，纯度和稳定性提高，2）最先进的首次超极化 人规模GE SPINlab 5 T仪器，3）动态核极化（DNP）的改进制剂， 潜在的更高的极化水平和更短的建立时间，以及4）使用 一种新的脉冲序列，采用多波段频谱空间射频（SSRF）脉冲激励的新的 MR/PET临床前成像平台（MR Solutions）。预计这些创新的累积影响将 提供了比最近有限的“概念证明”工作多一个数量级的灵敏度增益， 推动HP [1，3 - 13 C2]AcAc成为评估线粒体健康的强大的新成像工具。 该工具将在良好表征的DN啮齿动物模型中进行评价，以直接检验HP [1- 10] 13 C]AcAc可在临床可检测的表现之前检测早期DN。最后，与FOA一致，我们 致力于制定明确的计划，与潜在用户共享新开发的“催化工具”（超过30个实验室， HP 13 C MRI的必要设备），包括共享化学合成和配制的所有方案， 以及分享所有的脉冲序列源代码，新的SSRF脉冲波形，以及在线研究的数据。

PROJECT SUMMARY Mitochondrial dysfunction is recognized as a key early driver for disease progression in diabetic nephropathy (DN), among other chronic diseases, yet there exist very few tools for non-invasive assessment of mitochondrial status. Given that DN is an important source of diabetes-related morbidity and mortality (through its impact on cardiovascular outcomes), the ability to better understand and potentially even predict the progression of patients with diabetes to DN could have a large impact on clinical management of diabetes. The purpose of this R21 proposal (“Catalytic Tool and Technology Development in Kidney, Urologic, and Hematologic Diseases”) is to develop a new imaging probe with mitochondria-specific reactivity for hyperpolarized (HP) 13C MRI, [1,3- 13C2]acetoacetate (AcAc), providing non-invasive readout of mitochondrial metabolic status. This mitochondria- targeted ketone body probe has several favorable features with respect to HP 13C technology including long T1 signal lifetime, low toxicity, and rapid cellular uptake, but also has major associated challenges which have hampered development. To address these, we propose several technical innovations including: 1) improved chemical synthesis with increased purity and stability, 2) first-ever hyperpolarization on the state-of-the-art human-scale GE SPINlab 5T instrument, 3) improved formulation for dynamic nuclear polarization (DNP) with potentially higher polarization levels and shorter buildup times, and 4) highly efficient data acquisition with a novel pulse sequence employing multi-band spectral-spatial radiofrequency (SSRF) pulse excitation on a new MR/PET preclinical imaging platform (MR Solutions). The cumulative impact of these innovations is expected to provide a sensitivity gain of more than an order of magnitude over recent limited “proof of concept” work, propelling HP [1,3-13C2]AcAc into a powerful new imaging-based tool for assessing mitochondrial health. The tool will be evaluated in a well-characterized rodent model of DN, to directly test the hypothesis that HP [1- 13C]AcAc can detect early DN prior to clinically detectable manifestations. Lastly, consistent with the FOA, we are committed to a clear plan for sharing the newly developed “Catalytic Tool” with potential users (>30 labs with the necessary equipment for HP 13C MRI), including sharing all protocols for chemical synthesis and formulation, as well as sharing all pulse sequence source code, novel SSRF pulse waveforms, and data from the study online.