Prevention and Treatment of Acute Kidney Injury

 描述（由申请人提供）：慢性肾脏疾病中的急性肾损伤（阿基）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。此外，需要新的治疗策略来满足阿基中安全有效的预防和损伤后应用的医学需求。我们最近提出并评估了新的基于图像的方法，用于使用全氟化碳纳米颗粒造影剂，采用氟（19 F）成像和光谱学，在体素的基础上映射肾内血容量和PO 2。我们还发现了近端肾小管损伤的新的高度特异性生物标志物（肌肌醇加氧酶：MIOx），可用于阿基的早期检测和管理。 我们现在试图将这些工具作为客观、非侵入性、定量的方法，在动物模型中评估肾脏炎症、凝血和缺氧随时间和空间的变化，以确定其潜在的更广泛的转化效用。越来越多的证据表明，炎症和凝血途径之间的相互作用在阿基中起着关键作用，这些努力的基本原理就出现了。这种血管损伤不仅导致肾血流量的总体减少，损害肾小球滤过，而且还导致局部灌注不足、延长的缺氧/缺血性损伤、坏死和细胞凋亡，损害肾小管细胞再生和修复。我们将设计和部署新的纳米颗粒治疗剂，这些治疗剂对选定的炎症信号通路（例如，NF？B，细胞凋亡：巴克/Bax和凝血酶/PAR-1），其提供了在早期和晚期阿基中可以是互补和协同的试剂（肽、siRNA）的局部持续释放，或者甚至当作为预防措施应用时。因此，我们的目标是：目标1。针对阿基中有前景的分子靶点（NF κ B、凝血酶、巴克/Bax）单独和组合部署选定的协同纳米颗粒剂，并确定对早期和晚期阿基的疗效，以及作为肾缺血/再灌注（I/R）损伤小鼠模型中的预防剂。AIM 2.在体内应用PFC NP的双1H/19 F MRI和光谱学来定量肾内血容量，PO 2和损伤肾脏中的炎症随时间的变化，并与近端肾小管损伤（MIOx）特异性的新生物标志物相结合，描述对纳米治疗的反应。

 DESCRIPTION (provided by applicant): Acute kidney injury (AKI) 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. Furthermore, novel therapeutic strategies are needed to meet the medical need for both safe and effective preventative and post-injury applications in AKI. We have recently proposed and evaluated new image based methods for mapping intrarenal blood volume and PO2 on a voxel- wise basis with perfluorocarbon nanoparticle contrast agents employing fluorine (19F) imaging and spectroscopy. We also have discovered new highly specific biomarkers of proximal tubular injury (myo-Inositol Oxygenase: MIOx) that can be applied for early detection and management of AKI. We now seek to define the potential broader translational utility of these tools as objective, noninvasive, quantitative approaches for assessing renal inflammation, coagulation, and hypoxia over time and space in animal models. The rationale for these efforts emerges from growing evidence that interactions among inflammatory and coagulation pathways play a pivotal role in AKI. Such vascular damage not only causes an overall reduction of renal blood flow that compromises glomerular filtration but also leads to regional perfusion deficits, extended hypoxic/ischemic injury, necrosi, and apoptosis that impair tubular cell regeneration and repair. We will design and deploy new nanoparticle therapeutic agents that are active against selected inflammatory signaling pathways (e.g., NF¿B, apoptosis: Bak/Bax, and thrombin/PAR-1) in unique and effective formulations that provide localized sustained release of agents (peptides, siRNA) that may be complementary and synergistic in early and advanced AKI, or even when applied as preventative measures. Accordingly our aims are to: AIM 1. Deploy selected and synergistic nanoparticle agents singly and in combination against promising molecular targets in AKI (NFkB, thrombin, Bak/Bax) and define efficacy for early and late AKI, and as preventive agents in a mouse model of renal ischemia/reperfusion (I/R) injury. AIM 2. Apply dual 1H/19F MRI and spectroscopy of PFC NP in vivo to quantify intrarenal blood volume, PO2, and inflammation in injured kidneys over time, and delineate responses to nanotherapies, in concert with new biomarkers specific for proximal tubular damage (MIOx).