Hyperpolarized 13C MRI of renal mitochondrial dysfunction

肾线粒体功能障碍的超极化 13C MRI

• 批准号: 10593424
• 负责人: Cornelius von Morze
• 金额: $ 19.69万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-21 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10593424
• 关键词: Acetoacetates; Address; Affect; Anions; Bolus Infusion; Cardiovascular system; Cell physiology; Chronic Disease; Chronic Kidney Failure; Clinical; Clinical Management; Clinical Markers; Contrast Media; Cryopreservation; Custom; Data; Detection; Development; Diabetes Mellitus; Diabetic Nephropathy; Disease Progression; Equipment; Esters; Formulation; Freezing; Functional disorder; Genetic Models; Goals; Head; Health; Hematological Disease; Human; Hydrolysis; Image; Imaging Techniques; Isotope Labeling; Ketone Bodies; Kidney; Kidney Diseases; Laboratories; Liquid substance; Magnetic Resonance Imaging; Measures; Medical Imaging; Metabolic; Mitochondria; Morbidity - disease rate; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Obesity; Outcome; Patients; Performance; Physiologic pulse; Physiological; Positron-Emission Tomography; Process; Production; Protocols documentation; Pyruvate; Rattus; Reaction; Research; Rodent Model; Role; Sampling; Scanning; Series; Signal Transduction; Source; Source Code; Technology; Testing; Time; Tissues; Toxic effect; Urologic Diseases; Work; base; beta-Hydroxybutyrate; chemical stability; chemical synthesis; clinical translation; data acquisition; density; design; diabetes management; diabetic; experimental study; imaging biomarker; imaging platform; imaging probe; improved; in vivo; innovation; instrument; mitochondrial dysfunction; mitochondrial metabolism; molecular imaging; mortality; novel; preclinical imaging; public health relevance; radio frequency; simulation; solute; spectroscopic imaging; technology development; tool; tool development; uptake

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.

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力 （DN）除其他慢性疾病外，很少有无创评估线粒体的工具 地位。鉴于DN是与糖尿病相关的发病率和死亡率的重要来源（通过其对 心血管结局），更好地理解甚至可能预测患者进展的能力 糖尿病到DN可能会对糖尿病的临床管理产生很大影响。此R21的目的 提案（“肾脏，泌尿科和血液学疾病的催化工具和技术开发”）是 开发具有线粒体特异性反应性超极化（HP）13C MRI的新成像探针，[1,3-- 13C2]乙酸乙酸酯（ACAC），提供了线粒体代谢状态的非侵入性读数。这个线粒体 - 靶向酮体探针在HP 13C技术方面具有几个有利的功能，包括长T1 信号寿命，低毒性和快速的细胞摄取，但也有主要的相关挑战 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 化学合成具有增加的纯度和稳定性，2）最先进的首先超极化 人尺度的GE SpinLab 5T仪器，3）改进的动态核极化公式（DNP），带有 潜在的更高的极化水平和较短的堆积时间，以及4）具有高效的数据采集 新型脉冲序列采用多波段光谱空间射频（SSRF）脉冲兴奋 MR/PET临床前成像平台（MR Solutions）。这些创新的累积影响有望 与最近有限的“概念证明”工作相比，提供超过数量级的灵敏度增益， 推动HP [1,3-13C2] ACAC成为一种强大的基于成像的新工具，用于评估线粒体健康。 该工具将在DN的特征化啮齿动物模型中进行评估，以直接检验HP的假设[1-- 13C] ACAC可以在临床可检测的表现之前检测到早期的DN。最后，与foa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（> 30个实验室 HP 13C MRI的必要设备），包括共享所有用于化学合成和配方的方案， 以及共享所有脉冲序列源代码，新型SSRF脉冲波形以及在线研究的数据。