Molecular Magnetic Resonance Imaging of Inflammation

炎症分子磁共振成像

• 批准号: 10440453
• 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
• 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/10440453
• 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; 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

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/摘要 非酒精性脂肪肝病（NAFLD）影响80至1亿美国公民。最常见的形式 该疾病是一种良性和非促进状况，称为非酒精性脂肪肝（NAFL）。但是，约20％ NALFD病例被归类为非酒精性脂肪性肝炎（NASH），这是一种炎症状况 通常发展为肝纤维化，肝硬化，最后发展为肝癌或肝癌。唯一的方法 NAFL与NASH区分开是通过侵入性活检，这很昂贵，这是不可忽视的严重风险 内部出血，因此不适合患者随访。活检不是实用的筛查工具，作为 结果纳什通常无法诊断直到发展为晚期疾病。有生存好处 预计未来几年将在早期诊断和许多NASH治疗学。非侵入性 迫切需要诊断纳什或监测治疗反应的方法。有 促进晚期纤维化和肝硬化的放射学诊断的进步，但没有方法可以对 肝脏炎症不变，先于疾病进展。 脊髓过氧化物酶（MPO）是用于nash鉴别诊断的潜在成像生物标志物。 MPO是分泌的 通过激活的中性粒细胞作为炎症微环境的一部分，转化活性氧 （ROS）由中性粒细胞呼吸产生成高度伤害的ROS，如高藻酸。 MPO高度 在发炎的肝脏的细胞外空间中丰富，但在健康组织中很少。 我们最近开发了一个小分子Fe基的MRI对比剂（FE-PYC3A），该剂经历了10倍 在存在ROS的情况下，松弛性（MR信号产生效力）的增加。这个前所未有的很大 通过氧化为Fe2+到Fe3+，可以实现松弛性的变化。 Fe2+离子是一种非常低效的放松剂，但 高旋转Fe3+是一种非常有效的放松剂。使用急性小鼠模型的初步成像实验 胰腺炎表明，Fe-Pyc3a几乎没有对健康组织的对比度增强，但很强 和急性发炎组织的选择性对比度。重要的是，对比度增强水平 与通过体内实验室定量确定的MPO活性水平显着和正相关（r = 0.95，p <0.0001）。 该建议重点是优化和验证氧化还原活性FE复合物作为MPO特异性对比度 肝脏MRI的特工。这项研究的最终目标是无创成像测试以区分患者 由于侵入性活检，患者的非核心NAFL将受益。即时输出 拟议的工作将是1）特定于急性炎症的MRI对比剂，2）可以区分发炎 小鼠中的脂肪肝与非脂肪肝脏，3）不显示临床前的安全信号。