Hyperpolarized 13C Metabolic MRI for Noninvasive Monitoring of Kidney Injury

超极化 13C 代谢 MRI 用于无创监测肾损伤

基本信息

批准号：
10288911
负责人：
Peder Eric Zufall Larson
金额：
$ 20.19万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-12 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10288911
关键词：
Acute Renal Failure with Renal Papillary Necrosis Address Adoption Allografting Bicarbonates Biological Markers Biopsy Bolus Infusion Calibration Cancer Patient Cell Respiration Chronic Chronic Kidney Failure Clinical Clinical Research Contrast Media Creatine Data Data Analyses Data Set Development Diabetic Nephropathy Diagnosis Energy Metabolism Ensure Enzymes Etiology Functional disorder Future Glycolysis Goals Hematological Disease Histopathology Human Image Imaging Device Impairment Inflammation Injections Injury Injury to Kidney Investigation Ischemia Kidney Kidney Diseases Label Lactate Dehydrogenase Link Magnetic Resonance Imaging Maps Measurement Measures Mediating Metabolic Metabolic Pathway Metabolism Methods Mitochondria Molecular Monitor Motivation Noise Organ Oxidative Phosphorylation Patient imaging Perfusion Play Production Public Health Pyruvate Pyruvate Metabolism Pathway Renal function Reperfusion Injury Reproducibility Resolution Role Scanning Serum Signal Transduction Site Study Subject Techniques Technology Testing Time Tissues Toxin United States Urologic Diseases base clinical care design human subject imaging modality imaging probe improved innovation innovative technologies intravital imaging kidney allograft kidney metabolism kinetic model metabolic imaging metabolomics mouse model non-invasive monitor novel pyruvate dehydrogenase radiological imaging renal ischemia response targeted treatment technology development tool tool development

项目摘要

The overarching goal of this project is to develop a kidney metabolic imaging tool based on hyperpolarized (HP) 13C pyruvate MRI to investigate kidney energy metabolism for noninvasive monitoring of human kidney injury. This is in response to PAR-20-140: Catalytic Tool and Technology Development in Kidney, Urologic, and Hematologic Diseases encouraging “innovative radiological or intravital imaging methods, or novel imaging probes for study of the kidney”. The kidney is a highly energy-dependent organ requiring mitochondrial oxidative metabolism for key renal functions. Increasing evidence indicates that a shift from pyruvate mitochondrial oxidative phosphorylation to glycolysis and lactate production plays a central role in many etiologies of kidney injury leading to chronic kidney disease, which represents a major public health problem in the United States. Notably, currently available clinical tests such as serum creatine are known to be insensitive for monitoring kidney injury, and better noninvasive tools are needed. HP 13C MRI is an innovative technology platform that provides unprecedented gains in sensitivity (>10,000-fold signal increase) for imaging 13C-labeled bio-molecules, thereby permitting rapid and noninvasive investigation of dynamic metabolic processes. We have shown in a murine model of kidney ischemia-reperfusion injury that HP 13C pyruvate MRI can monitor the impaired mitochondrial pyruvate dehydrogenase (PDH) activity and the shift from oxidative metabolism to glycolysis in injured kidneys. Importantly, HP 13C pyruvate as a contrast agent has already been shown to be safe in initial cancer patient studies. However, human kidney studies with this approach require kidney-specific technology development. We propose to develop imaging tools to enable increased sensitivity to multiple metabolic pathways including PDH-mediated conversion to bicarbonate that is limited in signal with current methods, to ensure reproducibility, and to address issues of high perfusion unique to the kidneys for metabolism quantification. For an initial demonstration study, we propose to image patients with kidney allograft in order to correlate HP 13C pyruvate MRI with histopathology from biopsies; this will enable understanding of the molecular underpinning of the imaging findings that will be important for developing future studies in various kidney diseases. This enabling technology has an outstanding potential to advance our understanding of energy metabolism in kidney disease, to improve its timely diagnosis and therapy monitoring for both clinical research and clinical care. The tools from this technology development project can be readily disseminated to other sites, allowing broader adoption of the technology for studying kidney disease.

该项目的总体目标是基于超极化（HP）13C丙酮酸MRI，研究无创代谢的肾脏能量代谢监测人类肾脏损伤。这是对Par-20-140：催化工具和技术的回应肾脏，泌尿科和血液学疾病的发展，鼓励“创新放射学或插入式成像方法，或用于肾脏研究的新型成像问题”。肾脏是高度的能量依赖性器官需要关键肾功能的线粒体氧化物代谢。增加证据表明，从丙酮酸线粒体氧化磷酸化转变为糖酵解和乳酸生产在许多肾损伤病因中起着核心作用，导致慢性肾脏疾病，代表了美国的一个主要公共卫生问题。值得注意的是，目前可用已知临床测试（例如血清创造）对监测肾脏损伤不敏感，并且更好需要无创工具。 HP 13C MRI是一个创新的技术平台，可提供成像13C标记的生物分子的灵敏度（> 10,000倍的信号增加）的前所未有的增益，从而允许对动态代谢过程的快速和无创研究。我们已经显示了在HP 13C丙酮酸MRI的肾脏缺血再灌注损伤的鼠模型中线粒体丙酮酸脱氢酶（PDH）活性受损，并从氧化代谢转移在受伤的孩子中糖酵解。重要的是，已经显示了HP 13C丙酮酸作为对比剂在初始癌症患者研究中安全。但是，使用这种方法的人类肾脏研究需要肾脏特异性技术开发。我们建议开发成像工具以增加对多种代谢途径的敏感性，包括PDH介导的转化为碳酸氢盐用当前方法限制信号，以确保可重复性并解决高灌注问题用于代谢定量的儿童独有的。对于最初的示范研究，我们建议图像患有肾脏同种异体移植的患者，以将HP 13C丙酮酸MRI与组织病理学相关活检；这将使人们能够理解成像发现的分子基础对于发展各种肾脏疾病的未来研究至关重要。这项促成技术具有促进我们对肾脏疾病中能量代谢的理解的杰出潜力，以改善临床研究和临床护理的及时诊断和治疗监测。此工具技术开发项目可以很容易地传播到其他站点，从而更广泛地采用研究肾脏疾病的技术。