QUANTIFYING KIDNEY INJURY AND INFLAMMATION WITH FLUORINE (19F) MRI

描述（由申请人提供）：慢性肾脏疾病中的急性肾损伤是一种常见的临床问题，发病率不断增加，死亡率高得令人无法接受，50多年来没有改善，并且没有特异性治疗。兴趣是热衷于追求的方法，量化结构和功能的破坏，在渐进的 慢性疾病和急性损伤，可能会提高敏感性，特异性和时间， 诊断肾损伤，并促进风险分层和/或提供预后信息 包括预测肾功能的恢复。我们认为，结合基于连续图像的局部血容量、氧合和炎症的功能和分子读数，可以增强这些新的尿液生物标志物，以充分量化肾脏风险状态，并评估慢性和急性疾病的治疗。我们建议探索和比较现有方法的替代方法，使用天然和分子靶向的全氟化碳纳米颗粒（PFC NPs），可以为慢性和急性肾脏疾病的诊断成像和药物输送提供许多优势。我们的初步结果表明，肾内氧合可以无创映射19 F MRI。通过循环PFC NPs的19 F信号强度的区域性降低直接检测到肾缺血-再灌注（I/R）损伤诱导的外髓血管无灌注。PFC纳米粒促进抗凝治疗可有效抑制肾血管的这种区域性非灌注。该提议是高度转化的，并且待开发的方法具有直接的临床测试和实施途径，因为靶向PFC NPs造影平台已经在FDA批准的临床试验中用于使用氟（19 F）MRI/MRS进行血管生成的分子成像。此外，双重、同时质子和氟成像方法基本上在临床3 T扫描仪上开发和实施，并准备好被任何制造商采用。因此，我们的目标是：目标1。PFC NPs的19 F MRI是使用肾缺血/再灌注（I/R）损伤的小鼠模型AIM 2绘制肾内血容量、PO 2和炎症的定量测量。使用19 F MRI在体内评价PPACK纳米粒对抑制肾内无灌注的作用PHS 398/2590（2004年9月修订版，2006年4月重新发布） 公共卫生相关性：慢性肾脏疾病合并急性肾损伤是一种常见的临床问题，发病率不断增加，死亡率高得令人无法接受，50多年来没有改善，并且没有特异性治疗。我们建议实施肾内血容量，氧合和炎症的连续非侵入性功能和分子成像读数，并开发纳米颗粒促进抗凝治疗，应加强慢性和急性肾脏疾病的诊断和治疗。该提案具有高度的转化性，待开发的方法具有直接的临床测试和实施途径。

DESCRIPTION (provided by applicant): Acute kidney injury in the face of chronic kidney disease is a frequent clinical problem with an increasing incidence, an unacceptably high mortality rate that has not improved in more than 50 years, and no specific treatment. Interest is keen for the pursuit of methods for quantifying structural and functional disruption in progressive chronic disease and acute injury that might improve the sensitivity, specificity, and time in which renal injury is diagnosed, and facilitate risk stratification and/or provide prognostic information including prediction of recovery of renal function. We contend that the combination of adjunctive image-based functional and molecular readouts of regional blood volume, oxygenation, and inflammation could enhance these new urinary biomarkers to fully quantify the renal risk state and evaluate therapy in both chronic and acute diseases. We propose to explore and compare an alternative approach to existing methods with the use of native and molecularly targeted perfluorocarbon nanoparticles (PFC NPs) that could offer numerous advantages for diagnostic imaging and drug delivery to chronic and acute kidney diseases. Our preliminary results showed intrarenal oxygenation could be non-invasively mapped by 19F MRI. Renal ischemia-reperfusion (I/R) injury induced outer medullary vascular non-perfusion was directly detected by regional reduction of 19F signal intensity from circulating PFC NPs. Such regional non-perfusion of renal vasculature was effectively inhibited by PFC NPs facilitated anticoagulation therapy. The proposal is highly translational and the methods to be developed have a direct path to clinical testing and implementation because the targeted PFC NPs contrast platform already is in FDA-approved clinical trials for molecular imaging of angiogenesis with fluorine (19F) MRI/MRS. Furthermore, the dual, simultaneous proton and fluorine imaging methods are fundamentally developed and implemented on a clinical 3T scanner, and ready for adoption by any manufacturer. Accordingly our aims are to: AIM 1. Validate 19F MRI of PFC NPs is a quantitative measure for mapping intrarenal blood volume, PO2, and inflammation using a mouse model of renal ischemia/reperfusion (I/R) injury AIM 2. Evaluate the effect of PPACK NPs on inhibiting intrarenal nonperfusion using 19F MRI in vivo PHS 398/2590 (Rev. 09/04, Reissued 4/2006) Page Continuation Format Page PUBLIC HEALTH RELEVANCE: Chronic renal disease combined with acute kidney injury is a frequent clinical problem with an increasing incidence, an unacceptably high mortality rate that has not improved in more than 50 years, and no specific treatment. We propose to implement adjunctive noninvasive functional and molecular imaging readouts of intrarenal blood volume, oxygenation, and inflammation and to develop a nanoparticle facilitated anticoagulation therapy that should enhance diagnosis and treatment of chronic and acute kidney diseases. The proposal is highly translational and the methods to be developed have a direct path to clinical testing and implementation.