Prevention and Treatment of Acute Kidney Injury

 描述(申请人提供)：面对慢性肾脏疾病的急性肾损伤(AKI)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。此外，需要新的治疗策略来满足在AKI中安全和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基于图像的新方法，利用氟(19F)成像和光谱分析，以体素为基础，使用全氟碳纳米颗粒造影剂来绘制肾内血容量和PO2。我们还发现了新的近端肾小管损伤的高度特异性生物标志物(肌醇加氧酶：MIOx)，可用于AKI的早期诊断和治疗。我们现在试图将这些工具的潜在更广泛的翻译效用定义为客观的、非侵入性的、定量的方法，用于评估动物模型中随时间和空间变化的肾炎症、凝血和缺氧。这些努力的基础是越来越多的证据表明，炎症和凝血途径之间的相互作用在AKI中发挥着关键作用。这种血管损伤不仅会导致损害肾小球滤过的肾血流量的整体减少，还会导致局部灌流不足、广泛的缺氧/缺血损伤、坏死和细胞凋亡，从而损害肾小管细胞的再生和修复。我们将以独特和有效的配方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，核因子B、细胞凋亡：BAK/BAX和凝血酶/PAR-1)具有活性，提供局部持续释放的试剂(多肽、siRNA)，在早期和晚期AKI中可能具有互补和协同作用，甚至在作为预防措施应用时也是如此。因此，我们的目标是：1.针对AKI中有希望的分子靶点(NFkB、凝血酶、Bak/Bax)，单独和联合部署选择和协同的纳米药物，确定对早期和晚期AKI的有效性，并在小鼠肾脏缺血/再灌注(I/R)损伤模型中作为预防药物。目的2.应用双1H/19F磁共振成像和体内PFC NP波谱定量检测肾内血流量、血氧饱和度和损伤肾脏的炎症反应，并结合新的近端肾小管损伤(MIOx)特异性生物标志物，描述纳米治疗的反应。

 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).