Molecular Magnetic Resonance Imaging of Inflammation

炎症分子磁共振成像

基本信息

批准号：
10180955
负责人：
Eric Michael Gale
金额：
$ 42.92万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10180955
关键词：
Acids Acute Affect American Benign Biochemical Biological Markers Biopsy Biopsy Specimen Blood Vessels Cells Chelating Agents Cirrhosis Clinical Complex Contrast Media Detection Diagnosis Diet Differential Diagnosis Disease Disease Progression Dissociation Dose Early Diagnosis Electronics Extracellular Space Fatty Liver Fibrosis Free Energy Goals Hemorrhage Histology Image In Vitro Inflammation Inflammatory Ions Kidney Kinetics Knockout Mice Laboratories Libraries Ligands Liver Liver Failure Liver Fibrosis Liver diseases Magnetic Resonance Imaging Malignant neoplasm of liver Mediating Metabolism Methods Molecular Molecular Weight Monitor Motion Mus Muscle Noise Output Oxidation-Reduction Oxidative Stress Oxides Pancreas Patients Periodicity Peroxidases Phase III Clinical Trials Plasma Radiology Specialty Rattus Reactive Oxygen Species Regimen Relaxation Research Respiration Risk Rotation Safety Screening procedure Signal Transduction Specificity Structure Subgroup Testing Therapeutic Time Tissues Toxic effect Toxicokinetics Transferrin Water Work Zinc Chloride acute pancreatitis advanced disease base biophysical properties chemical synthesis contrast enhanced db/db mouse detection sensitivity experimental study follow-up imaging biomarker in vivo inhibitor/antagonist lead candidate liver imaging liver inflammation macrophage molecular imaging mouse model neutrophil non-alcoholic fatty liver non-alcoholic fatty liver disease non-invasive imaging nonalcoholic steatohepatitis oxidation potential biomarker preclinical safety prospective response screening small molecule treatment response

项目摘要

Project Abstract/ Summary Non-alcoholic fatty liver disease (NAFLD) affects between 80 to 100 million US citizens. The most common form of the disease is a benign and non-progressive condition called non-alcoholic fatty liver (NAFL). However, ~20% of NALFD cases are classified as non-alcoholic steatohepatitis (NASH), an inflammatory condition that commonly progresses to liver fibrosis, cirrhosis, and finally to liver failure or liver cancer. The only way to differentiate NAFL from NASH is via invasive biopsy which is expensive, poses a non-negligible risk of serious internal bleeding, and is thus ill-suited for patient follow-up. Biopsy is not a practical screening tool and as a result NASH typically goes undiagnosed until progression to advanced disease. There is a survival benefit to early diagnosis and a number of NASH therapeutics are anticipated within the next few years. Non-invasive methods to either diagnose NASH, or to monitor treatment response are sorely needed. There have been advances toward radiologic diagnosis of advanced fibrosis and cirrhosis but there are no methods to image the liver inflammation that invariantly precedes disease progression. Myeloperoxidase (MPO) is a potential imaging biomarker for differential diagnosis of NASH. MPO is secreted by activated neutrophils as part of the inflammatory microenvironment and converts reactive oxygen species (ROS) generated by neutrophil respiration into highly injurious ROS like perchlorous acid. MPO is highly abundant in the extracellular space of inflamed liver, but is scarce in healthy tissue. We recently developed a small molecule Fe-based MRI contrast agent (Fe-PyC3A) that undergoes a 10-fold increase in relaxivity (MR signal generating potency) in the presence of ROS. This unprecedentedly large relaxivity change is achieved by oxidation of Fe2+ to Fe3+. The Fe2+ ion is a very inefficient relaxation agent but high-spin Fe3+ is a very potent relaxation agent. Preliminary imaging experiments using a mouse model of acute pancreatitis demonstrate that Fe-PyC3A provides little-to-no contrast enhancement of healthy tissue but strong and selective contrast-enhancement of acutely inflamed tissue. Importantly, the level of contrast enhancement correlates significantly and positively with MPO activity levels determined by ex vivo laboratory quantitation (r = 0.95, P < 0.0001). This proposal focuses on optimizing and validating redox active Fe complexes as MPO-specific contrast agents for liver MRI. The ultimate goal of this research is a non-invasive imaging test to differentiate patients with non-progressive NAFL from patients will benefit from invasive biopsy. The immediate outputs of the proposed work will be an MRI contrast agent that is 1) specific to acute inflammation, 2) can differentiate inflamed vs. non-inflamed fatty liver in mice, and 3) does not exhibit pre-clinical safety signals.

项目摘要/总结非酒精性脂肪肝 (NAFLD) 影响着 80 至 1 亿美国公民。最常见的形式该疾病的本质是一种良性非进展性疾病，称为非酒精性脂肪肝 (NAFL)。然而，~20% 的 NALFD 病例被归类为非酒精性脂肪性肝炎 (NASH)，这是一种炎症性疾病，通常进展为肝纤维化、肝硬化，最后发展为肝功能衰竭或肝癌。唯一的方法是区分 NAFL 和 NASH 是通过侵入性活检进行的，这种活检费用昂贵，并且存在不可忽视的严重风险内出血，因此不适合患者随访。活检并不是一种实用的筛查工具，结果 NASH 通常不会被诊断出来，直到进展为晚期疾病。对生存有好处预计在未来几年内将出现早期诊断和多种 NASH 治疗方法。非侵入性迫切需要诊断 NASH 或监测治疗反应的方法。曾经有过晚期纤维化和肝硬化的放射学诊断取得了进展，但尚无方法对纤维化和肝硬化进行成像肝脏炎症总是先于疾病进展。髓过氧化物酶（MPO）是鉴别诊断 NASH 的潜在影像学生物标志物。 MPO 分泌由活化的中性粒细胞作为炎症微环境的一部分并转化活性氧中性粒细胞呼吸产生的活性氧（ROS）转化为高伤害性活性氧，如高氯酸。 MPO 高度发炎肝脏的细胞外空间中丰富，但在健康组织中很少。我们最近开发了一种小分子铁基 MRI 造影剂 (Fe-PyC3A)，经过 10 倍在存在 ROS 的情况下，弛豫度（MR 信号生成能力）增加。这个前所未有的大弛豫度变化是通过 Fe2+ 氧化为 Fe3+ 来实现的。 Fe2+ 离子是一种非常低效的弛豫剂，但高自旋 Fe3+ 是一种非常有效的弛豫剂。使用急性脑炎小鼠模型进行初步成像实验胰腺炎证明 Fe-PyC3A 对健康组织的对比度增强作用很小甚至没有，但效果很强以及急性炎症组织的选择性对比增强。重要的是，对比度增强的级别与体外实验室定量测定的 MPO 活性水平呈显着正相关 (r = 0.95，P < 0.0001）。该提案的重点是优化和验证氧化还原活性铁配合物作为 MPO 特异性对比肝脏 MRI 制剂。这项研究的最终目标是通过非侵入性成像测试来区分患者患有非进行性NAFL的患者将从侵入性活检中受益。的直接输出拟议的工作将是一种 MRI 造影剂，它 1) 特异性针对急性炎症，2) 可以区分炎症与小鼠非炎症性脂肪肝相比，3) 没有表现出临床前安全信号。