Prevention and Treatment of Acute Kidney Injury

急性肾损伤的预防和治疗

• 批准号: 9038362
• 负责人: SAMUEL A WICKLINE
• 金额: $ 29.83万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9038362
• 关键词: Acute; Acute Renal Failure with Renal Papillary Necrosis; Aging; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Anticoagulants; Apoptosis; Apoptotic; Arthritis; Biological Markers; Blood Vessels; Blood Volume; Cardiovascular Diseases; Cells; Chronic; Chronic Disease; Chronic Kidney Failure; Classification; Clinical; Coagulation Process; Combined Modality Therapy; Consumption; Contrast Media; Creatinine; Cytoprotection; Data; Development; Diagnosis; Disease; Dose-Limiting; Drug Delivery Systems; Drug Targeting; Early Diagnosis; Elderly; Evaluation; Evolution; Exhibits; Extravasation; Fluorine; Fluorocarbons; Formulation; Functional Imaging; Functional disorder; Funding; Goals; Health; Healthcare; Hemorrhage; Hypoxia; Image; Imaging Device; Immune; Incidence; Inflammation; Inflammatory; Injury; Intervention; Kidney; Kidney Diseases; Ligands; Magnetic Resonance Imaging; Malignant Neoplasms; Maps; Mediating; Medical; Methods; Molecular Target; Morbidity - disease rate; Natural regeneration; Necrosis; Output; Oxygen; Pathway interactions; Patients; Peptides; Perfusion; Play; Prevention; Preventive; Preventive measure; Progress Reports; Recovery; Regional Perfusion; Renal Blood Flow; Renal function; Reperfusion Injury; Resources; Risk; Role; Sensitivity and Specificity; Signal Pathway; Signal Transduction; Small Interfering RNA; Sorting - Cell Movement; Spectrum Analysis; Staging; Stratification; Syndrome; System; Therapeutic Agents; Thrombin; Thrombosis; Time; Tissues; Tracer; Tubular formation; Urine; Work; autocrine; base; clinical application; cytokine; design; flexibility; glomerular filtration; imaging modality; improved; in vivo; individual patient; injured; inositol oxygenase; insight; interest; kidney cell; meetings; meter; molecular imaging; mortality; mouse model; nanomedicine; nanoparticle; nanosystems; nanotherapy; non-invasive imaging; novel; novel therapeutics; paracrine; prognostic; prophylactic; quantitative imaging; renal ischemia; repaired; response; specific biomarkers; spectroscopic imaging; success; targeted treatment; tool

 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).

 描述（申请人提供）：慢性肾病引起的急性肾损伤（AKI）是临床常见问题，发病率不断上升，死亡率高得令人难以接受，50多年来没有改善，而且没有特效治疗方法。人们热衷于追求量化渐进结构和功能破坏的方法 慢性疾病和急性损伤可能会提高敏感性、特异性和时间 诊断肾损伤，并促进风险分层和/或提供预后信息 此外，需要新的治疗策略来满足 AKI 安全有效的预防和损伤后应用的医疗需求，我们最近提出并评估了基于图像的新方法，用于绘制肾内血容量和肾功能。采用氟 (19F) 成像和光谱学的全氟化碳纳米粒子造影剂在体素基础上的 PO2 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（肌醇）。加氧酶：MIOx）可用于 AKI 的早期检测和管理，我们现在寻求定义这些工具的潜在更广泛的转化效用，作为评估肾脏炎症、凝血和缺氧随时间和空间变化的客观、无创、定量方法。这些努力的理由来自于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肾血流量的整体减少，从而损害肾小球。过滤，但也会导致局部灌注不足、长期缺氧/缺血性损伤、坏死和细胞凋亡，从而损害肾小管细胞的再生和修复。我们将设计和部署新的纳米颗粒治疗剂，这些药物对选定的炎症信号传导途径（例如 NF¿）具有活性。 B、细胞凋亡：Bak/Bax 和凝血酶/PAR-1）采用独特且有效的配方，可提供局部持续释放的药物（肽、siRNA），这些药物在早期和晚期 AKI 中可能是互补和协同的，甚至在用作预防性药物时也是如此因此，我们的目标是： 目标 1. 针对 AKI（NFkB、凝血酶、Bak/Bax）和 AKI 中的有希望的分子靶点单独或组合部署选定的协同纳米颗粒制剂。定义早期和晚期 AKI 的疗效，以及作为肾缺血/再灌注 (I/R) 损伤小鼠模型的预防药物 AIM 2。应用双 1H/19F MRI 和体内 PFC NP 光谱来量化肾内血量，随着时间的推移，PO2 和受损肾脏的炎症，并描述对纳米疗法的反应，与近端肾小管损伤 (MIOx) 特异性的新生物标志物相结合。