Prevention and Treatment of Acute Kidney Injury

急性肾损伤的预防和治疗

• 批准号: 9269194
• 负责人: SAMUEL A WICKLINE
• 金额: $ 50.31万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9269194
• 关键词: Acute; Acute Renal Failure with Renal Papillary Necrosis; Aging; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Anticoagulants; Antithrombins; 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; Drug Delivery Systems; Drug Formulations; Drug Targeting; Early Diagnosis; Elderly; Evaluation; Evolution; Exhibits; Extravasation; Fluorine; Fluorocarbons; Formulation; Functional Imaging; Functional disorder; Funding; Goals; Healthcare; Hemorrhage; Hypoxia; Image; Imaging Device; Impairment; 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; Risk stratification; Role; Sensitivity and Specificity; Signal Pathway; Signal Transduction; Small Interfering RNA; Spectrum Analysis; Staging; Syndrome; System; Therapeutic Agents; Thrombin; Thrombosis; Time; Tissues; Tracer; Tubular formation; Urine; Work; autocrine; base; clinical application; cytokine; design; flexibility; glomerular filtration; imaging modality; immune function; improved; in vivo; individual patient; injured; inositol oxygenase; insight; interest; kidney cell; meter; molecular imaging; mortality; mouse model; nanomedicine; nanoparticle; nanosystems; nanotherapy; non-invasive imaging; novel; novel therapeutics; paracrine; prognostic; prophylactic; public health relevance; 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（由适用提供）：面对慢性肾脏疾病的急性肾脏损伤（AKI）是一个经常发生的临床问题，发病率增加，高死亡率高50年以上没有提高，没有特定的治疗方法。兴趣渴望追求量化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 诊断出肾脏伤害并促进风险分层和/或提供预后信息 包括预测肾功能的恢复。此外，还需要采取新颖的治疗策略来满足AKI中安全有效的预防和伤害后应用的医疗需求。我们最近提出并评估了新的基于图像的方法，用于与全氟化合物纳米粒子对比剂使用氟（19F）成像和光谱法的全氟纳米粒子对比剂，以素内绘制肾内血容量和PO2。我们还发现了新的高度特异性生物标志物的近端管状损伤（肌醇氧酶：miox），可用于早期检测和管理AKI。现在，我们试图将这些工具的潜在更广泛的转化效用定义为在动物模型中随时间和空间评估肾脏感染，凝结和缺氧的客观，无创的定量方法。这些努力的理由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中起着关键作用。这种血管损伤不仅会导致肾流动的总体减少，从而损害肾小球过滤，还导致区域灌注不足，延长的低氧/缺血性损伤，坏死和凋亡，损害结核细胞再生和修复。我们将设计和部署新的纳米颗粒治疗剂，这些治疗剂具有独特且有效的公式，这些剂（例如NF¿B，凋亡：BAK/BAX和凝血酶/PAR-1）具有独特而有效的配方，这些配方可提供局部化的持续释放（peptides，sirna，sirna，sirna，sirna），以供应及其早期和早期及其早期和早期的仪式。根据我们的目的，是：目标1。单独部署选定和协同的纳米颗粒剂，并结合AKI（NFKB，凝血酶，Bak/Bax）中有前途的分子靶标，并定义AKI早期和晚期的效率，以及在肾脏reschemia/Repererfusion的小鼠模型中受到预防代理（I//re）。 AIM 2。在体内使用双1H/19F MRI和PFC NP的双重光谱，以量化受伤肾脏的肾内血容量，PO2和炎症，并随着时间的推移与纳米疗法的反应，与针对近端管状损伤的新生物标志物（MIOX）一致。