Prevention and Treatment of Acute Kidney Injury

急性肾损伤的预防和治疗

• 批准号: 8886709
• 负责人: SAMUEL A WICKLINE
• 金额: $ 51.32万
• 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 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8886709
• 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 Formulations; Drug Targeting; Early Diagnosis; Elderly; Evaluation; Evolution; Exhibits; Extravasation; Fluorine; Fluorocarbons; Functional Imaging; Functional disorder; Funding; Goals; Health; Healthcare; Hemorrhage; Hypoxia; Image; Imaging Device; Immune; Incidence; Individual; Inflammation; Inflammatory; Injury; Intervention; Kidney; Kidney Diseases; Ligands; Magnetic Resonance Imaging; Malignant Neoplasms; Maps; Measures; Mediating; Medical; Methods; Molecular Target; Morbidity - disease rate; Natural regeneration; Necrosis; Output; Oxygen; Pathway interactions; Patients; Peptides; Perfusion; Play; Prevention; Preventive; 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; 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; spectroscopic imaging; success; therapeutic target; 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., NFκB, 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).

DESCRIPTION（由申请人提供）：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进步