Hyperpolarized 13C MRI of renal mitochondrial dysfunction

肾线粒体功能障碍的超极化 13C MRI

• 批准号: 10707325
• 负责人: Cornelius von Morze
• 金额: $ 23.33万
• 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/10707325
• 关键词: Acetoacetates; Address; Affect; Anions; Assessment tool; 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; Early Diagnosis; Equipment; Esters; Formulation; Freezing; Functional disorder; Genetic Models; Glass; 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; absorption; 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; non-invasive imaging; 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.

项目概要 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）等慢性疾病，但用于线粒体非侵入性评估的工具非常少 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），更好地理解甚至可能预测患者病情进展的能力 患有糖尿病的 DN 可能会对糖尿病的临床管理产生重大影响。 R21 的目的。 提案（“肾脏、泌尿科和血液疾病的催化工具和技术开发”）的目的是 开发一种具有线粒体特异性反应性的新型成像探针，用于超极化 (HP) 13C MRI，[1,3- 13C2]乙酰乙酸 (AcAc)，提供线粒体代谢状态的非侵入性读数。 相对于 HP 13C 技术，靶向酮体探针具有几个有利的特性，包括长 T1 信号寿命、低毒性和快速细胞摄取，但也面临着重大的相关挑战 为了解决这些问题，我们提出了几项技术创新，包括：1）改进。 化学合成具有更高的纯度和稳定性，2) 首次采用最先进的超极化技术 人体规模的 GE SPINlab 5T 仪器，3) 改进的动态核极化 (DNP) 配方 潜在更高的偏振水平和更短的建立时间，以及4）高效的数据采集 新颖的脉冲序列采用多频带频谱空间射频（SSRF）脉冲激励在一个新的 MR/PET 临床前成像平台（MR 解决方案）预计将产生这些创新的累积影响。 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 成为一种强大的新型基于成像的工具，用于评估线粒体健康状况。 该工具将在一个充分表征的 DN 啮齿动物模型中进行评估，以直接检验 HP [1- 13C]AcAc 可以在临床可检测到的表现之前检测到早期 DN 最后，与 FOA 一致，我们。 致力于制定一个明确的计划，与潜在用户（超过 30 个实验室）分享新开发的“催化工具” HP 13C MRI 的必要设备），包括共享化学合成和配方的所有协议， 以及共享所有脉冲序列源代码、新颖的 SSRF 脉冲波形和在线研究数据。