Hyperpolarized 13C MRI of renal mitochondrial dysfunction

项目总结 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 在其他慢性疾病中，线粒体的非侵入性评估工具很少 状态。鉴于糖尿病肾病是糖尿病相关发病率和死亡率的重要来源(通过其对 心血管结果)，更好地理解甚至潜在地预测患者的进展的能力 糖尿病合并糖尿病肾病可能会对糖尿病的临床治疗产生很大影响。这款R21的用途 建议(“肾脏、泌尿外科和血液系统疾病的催化工具和技术发展”)是 开发一种具有线粒体特异性反应的新型超极化(HP)13C磁共振成像探针，[1，3- 13C2]乙酰乙酸酯(Acac)，提供线粒体代谢状态的非侵入性读数。这个线粒体- 与HP 13C技术相比，靶向酮体探头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，但也存在重大相关挑战 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 提高纯度和稳定性的化学合成，2)有史以来最先进的超极化 人尺度GE SpinLab 5T仪器，3)改进的动态核极化(DNP)公式 潜在更高的偏振水平和更短的积累时间，以及4)高效的数据采集 一种采用多频段频谱-空间射频(SSRF)脉冲激励的新型脉冲序列 MR/PET临床前成像平台(MR解决方案)。这些创新的累积影响预计将 与最近有限的“概念验证”工作相比，灵敏度提高了一个数量级以上， 推动HP[1，3-13C2]acac成为一种强大的基于成像的评估线粒体健康的新工具。 该工具将在一个具有良好特征的糖尿病肾病啮齿动物模型中进行评估，以直接测试HP[1- 13C]ACAC可以在临床可检测到的表现之前发现早期的糖尿病肾病。最后，与《全面和平协议》相一致，我们 致力于与潜在用户共享新开发的“催化工具”的明确计划(&gt；30个实验室，具有 HP 13C MRI的必要设备)，包括共享化学合成和配方的所有方案， 以及在线共享所有脉冲序列源代码、新颖的SSRF脉冲波形和研究数据。

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.