Noninvasive Nephritis Imaging

项目摘要/摘要。 炎症在许多肾脏疾病状态中起着关键的致病作用。相应地，程序以 诊断、映射和纵向监测肾脏炎症可以极大地提高我们识别和 治疗与药物毒性、缺血、感染、自身免疫性疾病有关的肾损伤患者，以及 移植物功能障碍。不幸的是，肾脏炎症的明确诊断需要活组织检查，这是 侵入性的，昂贵的，构成了巨大的出血风险，并且只对肾脏的一小部分进行了采样。重复活组织检查 对于纵向患者监测是不切实际的。此外，许多需要活组织检查的患者 禁忌症包括肥胖、抗凝、严重高血压或单肾。 迫切需要非侵入性地检测、标测、量化和监测许多 肾脏疾病状态。目前可用的成像技术可以潜在地识别肾脏 炎症，如[18F]氟-2-脱氧葡萄糖(FDG)正电子发射断层扫描(PET)有重要意义 局限性，缺乏足够的空间分辨率来绘制疾病地图，使患者暴露在电离辐射中，以及 事实上，FDG既在肾脏排泄，又在近端小管中部分被重新吸收，这一事实削弱了对 实质炎性浸润物。实验用超小顺磁性氧化铁纳米颗粒(USPIONS) 以吞噬细胞为靶点已在临床试验中用于成像肾脏炎症，但这种方法是 受美国药代动力学缓慢的限制，在注射和成像读数之间需要几天的时间。 一种理想的肾脏炎症分子成像技术应该不会产生背景信号 肾脏，在存在炎症的情况下产生阳性信号增强，并产生炎症- 在注射后几分钟内进行特定的成像读数。我们假定我们可以满足这些技术标准 使用新近发明的新型活性氧簇(ROS)响应型磁共振成像探针 我们的实验室。细胞外ROS浓度升高是炎症组织的一个显著特征，如粒细胞 先天免疫系统的细胞经历呼吸爆发，导致异常氧化组织 微环境。我们的ROS特异性造影剂Fe-PyC3A是一种低分子铁络合物， 在存在ROS的情况下瞬间在MR静默状态和MR可见状态之间切换。 此R21的目标是通过演示来促进Fe-PyC3A作为肾脏炎症成像工具的发展 在小鼠缺血和免疫相关肾脏疾病模型中的概念验证，优化剂量 肾脏磁共振成像，并证明肾脏成像应用的安全性。这份建议书是写在 肾脏、泌尿外科和血液学对PAR-20-140“催化工具和技术开发”的响应 疾病“，并特别针对”创新的新放射学方法和新的成像探头“的呼吁。 排斥模型中的肾间隔区。

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.