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

描述(申请人提供)：面对慢性肾脏疾病的急性肾损伤是一个常见的临床问题，发病率不断上升，死亡率高得令人无法接受，50多年来一直没有改善，也没有具体的治疗方法。人们热衷于寻求量化渐进性结构和功能障碍的方法 慢性疾病和急性损伤，可能会提高敏感性、特异性和时间 肾损伤得到诊断，便于风险分层和/或提供预后信息 包括对肾功能恢复的预测。我们认为，基于辅助图像的局部血容量、氧合和炎症的功能和分子读数的结合可以增强这些新的尿液生物标志物，以全面量化肾脏风险状态，并评估慢性和急性疾病的治疗。我们建议探索和比较一种替代现有方法的方法，使用天然的和分子靶向的全氟碳纳米颗粒(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，19F MRI可以无创性地标测肾内的氧合作用。通过局部降低循环PFC NPs的~(19)F信号强度，直接检测肾缺血-再灌注损伤所致的外髓血管无灌流。PFC纳米粒促进的抗凝治疗有效地抑制了这种区域性的肾血管非灌注性。该提案具有很高的翻译性，而且将要开发的方法具有直接的临床测试和实施途径，因为定向PFC NPs造影剂平台已经在FDA批准的使用氟(19F)MRI/MRS进行血管生成分子成像的临床试验中。此外，双质子和氟成像方法是从根本上开发的，并在临床3T扫描仪上实施，可供任何制造商采用。因此，我们的目标是：1.利用小鼠肾缺血/再灌注(I/R)损伤模型，验证PFC纳米粒的19F磁共振成像是一种定量测量肾内血容量、氧分压和炎症的方法。目的2.使用19F MRI in vivo PHS 398/2590(版本09/04，重新发布4/2006)页面延续格式来评价PPACK纳米粒抑制肾内非灌注的作用。 公共卫生相关性：慢性肾脏疾病合并急性肾损伤是一个常见的临床问题，发病率不断上升，死亡率高得令人无法接受，50多年来一直没有改善，也没有具体的治疗方法。我们建议实施肾内血容量、氧合和炎症的辅助非侵入性功能和分子成像读数，并开发一种纳米颗粒促进的抗凝治疗，该疗法应有助于慢性和急性肾脏疾病的诊断和治疗。该提案具有很高的翻译性，所开发的方法有一条通往临床测试和实施的直接途径。

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.