Noninvasive Nephritis Imaging

无创性肾炎成像

• 批准号: 10490328
• 负责人: Eric Michael Gale
• 金额: $ 25.08万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-21 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10490328
• 关键词: Acute; Address; Allografting; Anticoagulation; Autoimmune Diseases; Biodistribution; Biopsy; Cells; Classification; Clinical Chemistry; Clinical Trials; Complex; Contralateral; Contrast Media; Data; Deoxyglucose; Diagnosis; Disease; Dose; Drug Kinetics; Drug toxicity; Evaluation; Extracellular Fluid; Functional disorder; General Hospitals; Goals; Hematology; Hemorrhage; Histologic; Hypertension; Image; Imaging Device; Imaging technology; Immune; Infection; Infiltration; Inflammation; Inflammatory Infiltrate; Injections; Injury; Injury to Kidney; Innate Immune System; Ionizing radiation; Iron; Ischemia; Kidney; Kidney Diseases; Kidney Transplantation; Knockout Mice; Label; Magnetic Resonance Imaging; Maps; Massachusetts; Methods; Modeling; Molecular Weight; Monitor; Mus; NADPH Oxidase; Nephritis; Obesity; Oxides; Pathogenicity; Patient Monitoring; Patients; Phagocytes; Play; Positron-Emission Tomography; Procedures; Radiology Specialty; Reactive Oxygen Species; Reperfusion Injury; Reperfusion Therapy; Resolution; Respiratory Burst; Risk; Role; Safety; Saline; Sampling; Signal Transduction; Technology; Tissues; Toxic effect; Transplantation; Tubular formation; Visualization; allograft rejection; base; cost; experimental study; extracellular; granulocyte; imaging probe; innovation; interstitial; iron oxide nanoparticle; kidney allograft; kidney imaging; macrophage; molecular imaging; mouse model; novel; post-transplant; renal damage; renal ischemia; response; technology development; tool development; urologic

Project Summary/Abstract. Inflammation plays a key pathogenic role in numerous kidney disease states. Accordingly, procedures to diagnose, map, and longitudinally monitor kidney inflammation can greatly enhance our ability to identify and treat patients suffering from kidney injury related to drug toxicity, ischemia, infection, autoimmune diseases, and allograft dysfunction. Unfortunately, definitive diagnosis of kidney inflammation requires biopsy, which is invasive, costly, poses substantial bleeding risk, and samples only a small segment of the kidney. Repeat biopsy is impractical for longitudinal patient monitoring. Furthermore, many patients requiring biopsy have contraindications including obesity, anticoagulation, severe hypertension, or single kidney. There is an urgent unmet need to noninvasively detect, map, quantify, and monitor inflammation in numerous kidney disease states. Currently available imaging technologies which could potentially identify kidney inflammation, such as [18F]fluoro-2-deoxyglucose (FDG) positron emission tomography (PET) have important limitations, lacking sufficient spatial resolution for disease mapping, exposing patients to ionizing radiation, and the fact that FDG is both renally excreted and partially reabsorbed in proximal tubules blunts visualization of parenchymal inflammatory infiltrates. Experimental ultrasmall paramagnetic iron-oxide nanoparticles (USPIONs) targeted to phagocytic cells have been used to image kidney inflammation in clinical trials, but this approach is limited by slow USPION pharmacokinetics, requiring several days between injection and imaging readout. An ideal technology for molecular imaging of kidney inflammation should generate no background signal in the kidney, generate positive signal enhancement in the presence of inflammation, and yield an inflammation- specific imaging readout within minutes of injection. We posit that we can satisfy these technologic criteria using new class of reactive oxygen species (ROS) responsive MR imaging probe recently invented by our lab. Elevated extracellular ROS concentrations are a hallmark feature of inflamed tissue, as granulocytic cells of the innate immune system undergo respiratory burst resulting in an aberrant oxidizing tissue microenvironment. Our ROS-specific contrast agent, Fe-PyC3A, is a low molecular weight iron complex that instantaneously switches between an MR silent and MR visible states in the presence ROS. The goals of this R21 are to advance Fe-PyC3A as tool for imaging kidney inflammation by demonstrating proof of concept in murine models of ischemia- and immune-related kidney diseases, optimizing the dose for kidney MR imaging, and demonstrating safety for kidney imaging applications. This proposal is written in response to PAR-20-140 “Catalytic Tool and Technology Development in Kidney, Urologic, and Hemotologic Diseases,” and specifically addresses calls for “innovative new radiologic methods and novel imaging probes.” kidney compartments in the rejection model.

项目摘要/摘要。 在众多肾脏疾病状态下，炎症起着关键的致病作用。根据诉讼，程序 诊断，地图和纵向监测肾脏注射可以大大增强我们识别和 治疗与药物毒性，缺血，感染，自身免疫性疾病和 同种异体功能障碍。不幸的是，对肾脏注射的明确诊断需要活检，即 侵入性，代价高昂，带来了大量出血的风险，样品仅肾脏的一小部分。重复活检 对于纵向患者监测是不切实际的。此外，许多需要活检的患者有 禁忌症，包括肥胖，抗凝，严重的高血压或单个肾脏。 在许多众多 肾脏疾病状态。目前可用的成像技术可能会识别肾脏 炎症，例如[18F] Fluoro-2-脱氧葡萄糖（FDG）极性发射断层扫描（PET）具有重要 局限性，缺乏足够的空间分辨率来用于疾病映射，使患者暴露于电离辐射以及 FDG既是肾脏排他性的，又是部分重吸收的，以近端管的可视化可视化 副炎性浸润。实验性超刺磁铁氧化纳米颗粒（USPIONS） 针对吞噬细胞的靶向细胞已用于在临床试验中对肾脏感染进行成像，但是这种方法是 受慢速USPION药代动力学的限制，需要在注射和成像读数之间进行几天。 肾脏感染分子成像的理想技术应在 肾脏在感染存在下产生正信号增强，并产生注射 - 注射几分钟内的特定成像读数。我们指出我们可以满足这些技术标准 使用新的一类活性氧（ROS）响应式MR成像探针最近发明了 我们的实验室。颗粒细胞升高的细胞外ROS浓度是发炎组织的标志性特征 先天免疫系统的细胞发生呼吸道爆发，导致异常氧化组织 微环境。我们的ROS特异性对比剂Fe-pyc3a是一种低分子量铁络合物， 在ROS存在的情况下，即时在Silent MR和MR可见状态之间切换。 该R21的目标是通过证明肾脏肾脏的肾脏注射工具 在缺血和免疫相关肾脏疾病的鼠模型中的概念证明，优化剂量 肾脏MR成像，并证明肾脏成像应用的安全性。该提案写在 对20-140 Par-20-140的反应“肾脏，泌尿科和血液学的催化工具和技术开发 疾病，并专门针对“创新的新放射学方法和新型成像问题”的呼吁。 拒绝模型中的肾脏室。