Noninvasive Nephritis Imaging

无创性肾炎成像

• 批准号: 10373279
• 负责人: Eric Michael Gale
• 金额: $ 20.88万
• 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 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10373279
• 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。 炎症在许多肾脏疾病中起着关键的致病作用。 诊断、绘制和纵向监测肾脏炎症可以极大地增强我们识别和诊断肾脏炎症的能力。 治疗因药物毒性、缺血、感染、自身免疫性疾病和相关肾损伤的患者 不幸的是，肾炎症的明确诊断需要活检。 侵入性、成本高昂、存在很大的出血风险，并且只能对肾脏的一小部分进行重复活检。 对于纵向患者监测来说是不切实际的。此外，许多需要活检的患者已经进行了活检。 禁忌症包括肥胖、抗凝、严重高血压或单肾。 在众多疾病中，对非侵入性检测、绘图、量化和监测炎症的迫切需求尚未得到满足。 目前可用的成像技术有可能识别肾脏疾病。 炎症，例如[18F]氟-2-脱氧葡萄糖（FDG）正电子发射断层扫描（PET）具有重要意义 局限性，缺乏足够的空间分辨率来绘制疾病图，使患者暴露在电离辐射下，以及 FDG 经肾脏排泄并在近端肾小管中部分重吸收，这一事实削弱了 实质炎症浸润。实验性超小型顺磁性氧化铁纳米颗粒（USPION） 针对吞噬细胞的研究已在临床试验中用于对肾脏炎症进行成像，但这种方法是 受到缓慢的 USPION 药代动力学的限制，注射和成像读出之间需要几天的时间。 肾脏炎症分子成像的理想技术应该不产生背景信号 肾脏，在存在炎症的情况下产生正信号增强，并产生炎症- 我们认为我们可以满足这些技术标准。 使用最近发明的新型活性氧 (ROS) 响应 MR 成像探头 我们的实验室认为，细胞外活性氧浓度升高是粒细胞炎症组织的一个标志性特征。 先天免疫系统的细胞经历呼吸爆发，导致异常的氧化组织 我们的 ROS 特异性造影剂 Fe-PyC3A 是一种低分子量铁络合物， 在存在 ROS 的情况下，立即在 MR 静音和 MR 可见状态之间切换。 该 R21 的目标是通过证明 Fe-PyC3A 作为炎症肾脏成像工具的发展 在缺血和免疫相关肾脏疾病的小鼠模型中进行概念验证，优化剂量 肾脏 MR 成像，并证明肾脏成像应用的安全性。 对 PAR-20-140“肾脏、泌尿和血液学催化工具和技术开发”的回应 疾病”，并特别呼吁“创新的放射学方法和新颖的成像探针”。 排斥模型中的肾室。