Perioperative high-density lipoproteins and postoperative AKI

围手术期高密度脂蛋白和术后 AKI

基本信息

批准号：
10391447
负责人：
Loren Elisa Smith
金额：
$ 17.57万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10391447
关键词：
Academic Medical Centers Activities of Daily Living Acute Renal Failure with Renal Papillary Necrosis Affect Anesthesiology Apolipoprotein A-I Award Bioinformatics Blood Blood Vessels Cardiac Cardiac Surgery procedures Cells Cessation of life Characteristics Chronic Kidney Failure Clinical Data Clinical Research Core Facility Creatinine Data Doctor of Philosophy Dose Endothelial Cells Endothelium Environment Enzyme-Linked Immunosorbent Assay Experimental Designs F2-Isoprostanes Faculty Fellowship Free Radicals Goals High Density Lipoprotein Cholesterol High Density Lipoproteins Hospitals Hour Human Hypoxia In Vitro Incubated Injury to Kidney Intercellular adhesion molecule 1 K-Series Research Career Programs Kidney Lecithin Lipid Peroxidation Lipoproteins Measurement Measures Mediating Mentors Mentorship Methods MicroRNAs Modeling Molecular Biology Mus Neutrophil Infiltration Operative Surgical Procedures Outcome Oxidative Stress Patients Perioperative Pharmacology Phenotype Plasma Postoperative Period Program Development Prospective Studies Proteins Proximal Kidney Tubules Rattus Renal tubule structure Reperfusion Injury Reperfusion Therapy Research Residencies Reverse Transcriptase Polymerase Chain Reaction Risk Serum Severities Stress Study Subject TLR2 gene TLR4 gene TNF gene Testing Therapeutic Time Tissue Inhibitor of Metalloproteinases Training Translational Research Tubular formation Universities Urine Vesicle Western Blotting atorvastatin base career career development experience experimental study high density lipoprotein-1 in vivo injury prevention insulin-like growth factor binding protein-related protein 1 miRNA expression profiling mouse model novel particle pre-clinical prevent prospective rat KIM-1 protein recruit renal damage renal ischemia sham surgery skills translational research program urinary

项目摘要

Project Abstract This award will support a prospective clinical study and the career development of Loren E. Smith, MD, PhD. Dr. Smith completed a PhD in high-density lipoprotein (HDL) molecular biology with Dr. Sean Davidson at the University of Cincinnati and residency training in Anesthesiology at Vanderbilt University Medical Center (VUMC), where she was appointed faculty in 2017. VUMC is a tertiary academic hospital renowned for its highly collaborative research environment, exceptional career development programs, and extensive core facilities. During her T32 fellowship Dr. Smith and her mentors, Drs. Linton, Billings, and Vickers, discovered an association between higher preoperative HDL and reduced AKI in cardiac surgery patients. In her proposed study, Dr. Smith will test the hypotheses that higher perioperative concentrations of apolipoprotein (apo) A-I and specific HDL-microRNAs (miRNAs) are associated with less postoperative AKI (Aim 1), that a higher HDL functional capacity to suppress endothelial cell intercellular adhesion molecule 1 (ICAM-1) and renal proximal tubule cell toll-like receptor (TLR) 2 and TLR4 expression is associated with less AKI (Aim 2), and that exogenous HDL administration to mice before renal ischemia and reperfusion (IR) reduces renal ICAM-1, TLR2, and TLR4 expression and AKI (Aim 3). Aims 1 and 2 will be tested in a 150-subject prospective study of patients undergoing cardiac or vascular surgery. Blood, urine, and clinical data will be collected longitudinally throughout the perioperative period. ApoA-I concentration will be determined with an ELISA; HDL-miRNAs will be isolated, sequenced and quantified with RT-PCR; and HDL functional capacity to suppress ICAM-1, TLR2, and TLR4 will be measured in vitro using human endothelial and renal proximal tubule cells stimulated with TNF-α and hypoxia respectively. Study subjects’ HDL characteristics will be compared to their severity of renal tubule stress and damage, quantified by urinary concentrations of tissue inhibitor of metalloproteinase 2, insulin-like growth factor- binding protein 7, and kidney injury molecule 1 and to their severity of AKI, quantified with 48-hour serum creatinine change from baseline using latent variable regression modeling. During Aim 3 studies, threedifferent doses of HDL particles will be administered to mice before renal IR injury or sham surgery, and the effects of HDL dose on renal damage will be quantified. In a second experiment, HDL containing different miRNAs will be administered before renal IR injury to determine the effect of specific HDL-miRNAs on AKI. By completing this study, Dr. Smith will obtain training in the management of a translational research team and in vivo experimental design from Dr. Linton; perioperative clinical study execution and AKI phenotyping from Dr. Billings; and HDL-associated microRNA (miRNA) sequencing and bioinformatics analysis from Dr. Vickers. In this manner, with the support of this career development award, her mentorship team, and her institutional environment, Dr. Smith will obtain the necessary skills to establish an independent translational research program focused on developing novel lipoprotein-based therapies to reduce postoperative AKI.

项目摘要该奖项将支持一项前瞻性临床研究和医学博士Loren E. Smith的职业发展。博士史密斯（Smith 辛辛那提大学和范德比尔特大学医学中心麻醉学居住培训（VUMC），她于2017年被任命为教职员工。VUMC是一家以其高度闻名协作研究环境，出色的职业发展计划和广泛的核心设施。在T32奖学金期间，史密斯博士和她的导师博士。林顿，比林斯和维克斯发现了一个术前HDL和心脏手术患者的AKI降低之间的关联。在她的提议中研究，史密斯博士将测试较高的周期性载脂蛋白（APO）A-I和特定的HDL-微虫（miRNA）与术后AKI较少有关（AIM 1），即HDL较高抑制内皮细胞间细胞间粘合分子1（ICAM-1）和肾脏近端的功能能力 Tubele细胞Toll样受体（TLR）2和TLR4表达与较少的AKI相关（AIM 2），并且外源性在肾脏缺血和再灌注之前对小鼠进行HDL给药（IR）减少了肾脏ICAM-1，TLR2和TLR4 表达和AKI（AIM 3）。目标1和2将在150个受试者的前瞻性研究中进行测试心脏或血管手术。在整个过程中，将纵向收集血液，尿液和临床数据周期性期。 ApoA-I浓度将通过ELISA确定； HDL mirnas将被隔离，用RT-PCR测序并定量；抑制ICAM-1，TLR2和TLR4的HDL功能能力将使用TNF-α和缺氧刺激的人类内皮和肾脏近端细胞细胞在体外测量研究对象的HDL特征将与其肾小管应力的严重程度进行比较损伤，通过金属蛋白酶2的组织抑制剂的尿浓度量化，胰岛素样生长因子 - 结合蛋白7和肾损伤分子1及其AKI的严重程度，用48小时的序列量化肌酐使用潜在变量回归建模从基线变化。在AIM 3研究中，三分化 HDL颗粒的剂量将在肾脏IR损伤或假手术之前对小鼠施用，HDL的作用肾脏损伤的剂量将被量化。在第二个实验中，包含不同miRNA的HDL将是在肾脏IR损伤之前进行给药，以确定特定的HDL-MIRNA对AKI的影响。通过完成这项研究，史密斯博士将获得翻译研究团队管理的培训， Linton博士的体内实验设计；来自博士的定期临床研究执行和AKI表型帐单；来自Vickers博士的HDL相关microRNA（miRNA）测序和生物信息学分析。在在这个职业发展奖的支持下，她的指导团队和她的机构环境，史密斯博士将获得建立独立翻译研究的必要技能计划致力于开发基于脂蛋白的新型疗法，以减少术后AKI。