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开发一种基于超极化 (HP) 13C 丙酮酸 MRI 用于无创研究肾脏能量代谢这是对 PAR-20-140 的回应：催化工具和技术。肾脏、泌尿系统和血液疾病的发展鼓励“创新放射学” 或活体成像方法，或用于肾脏研究的新型成像探针”。能量依赖性器官需要线粒体氧化代谢来维持关键的肾功能。有证据表明线粒体从丙酮酸氧化磷酸化转变为糖酵解和乳酸的产生在导致慢性肾病的许多肾损伤病因中起着核心作用值得注意的是，这是目前美国的一个主要公共卫生问题。已知血清肌酸等临床测试对于监测肾损伤不敏感，并且更好 HP 13C MRI 是一个创新的技术平台，可提供非侵入性工具。 13C 标记生物分子成像的灵敏度前所未有地提高（信号增加 >10,000 倍），从而允许对动态代谢过程进行快速和无创的研究。在小鼠肾脏缺血再灌注损伤模型中，HP 13C 丙酮酸 MRI 可以监测线粒体丙酮酸脱氢酶 (PDH) 活性受损以及氧化代谢的转变重要的是，HP 13C 丙酮酸作为造影剂已被证明。在最初的癌症患者研究中是安全的然而，使用这种方法的人体肾脏研究需要。我们建议开发成像工具以提高肾脏特异性。对多种代谢途径的敏感性，包括 PDH 介导的碳酸氢盐转化，即当前方法的信号有限，以确保重现性并解决高灌注问题对于肾脏代谢定量而言，我们建议进行初步示范研究。对同种异体肾移植患者进行成像，以便将 HP 13C 丙酮酸 MRI 与组织病理学相关联活检；这将有助于了解成像结果的分子基础这项技术对于开展各种肾脏疾病的未来研究非常重要。促进我们对肾脏疾病能量代谢的理解、改善肾脏疾病的巨大潜力其用于临床研究和临床护理的及时诊断和治疗监测工具。技术开发项目可以很容易地传播到其他站点，从而可以更广泛地采用研究肾脏疾病的技术。