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：
10614975
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/10614975
关键词：
Academic Medical Centers Activities of Daily Living Acute Renal Failure with Renal Papillary Necrosis Affect Anesthesiology Apolipoprotein A-I Apolipoproteins 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 IGFBP2 gene In Vitro Incubated Injury to Kidney Institution Intercellular adhesion molecule 1 Ischemia 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 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 career career development experience experimental study high density lipoprotein-1 in vivo injury prevention insulin-like growth factor binding protein-related protein 1 ischemic injury miRNA expression profiling mouse model novel particle pharmacologic 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医学博士 Loren E. Smith 的前瞻性临床研究和职业发展。史密斯 (Smith) 与肖恩·戴维森 (Sean Davidson) 博士一起在该大学完成了高密度脂蛋白 (HDL) 分子生物学博士学位辛辛那提大学和范德比尔特大学医学中心麻醉学住院医师培训（VUMC），她于 2017 年被任命为教员。VUMC 是一家三级学术医院，以其高度的声誉而闻名。协作研究环境、卓越的职业发展计划以及广泛的核心设施。在 T32 奖学金期间，史密斯博士和她的导师林顿博士、比林斯博士和维克斯博士发现了一个问题。心脏手术患者术前较高的 HDL 与 AKI 降低之间的关联。在这项研究中，Smith 博士将测试以下假设：载脂蛋白 (apo) A-I 和围手术期浓度较高特定 HDL-microRNA (miRNA) 与较少的术后 AKI 相关（目标 1），即较高的 HDL 抑制内皮细胞细胞间粘附分子 1 (ICAM-1) 和肾近端的功能能力小管细胞 Toll 样受体 (TLR) 2 和 TLR4 表达与较少的 AKI 相关（目标 2），并且外源性肾缺血再灌注 (IR) 前给小鼠施用 HDL 会降低肾 ICAM-1、TLR2 和 TLR4 表达和 AKI（目标 3）将在一项 150 名受试者的前瞻性研究中进行测试。将在整个过程中纵向收集血液、尿液和临床数据。围手术期将通过 ELISA 测定 ApoA-I 浓度；通过 RT-PCR 进行测序和定量；并且 HDL 抑制 ICAM-1、TLR2 和 TLR4 的功能能力将使用 TNF-α 和缺氧刺激的人内皮细胞和肾近曲小管细胞进行体外测量研究对象的 HDL 特征将分别与其肾小管应激的严重程度进行比较。损伤，通过尿液中金属蛋白酶 2 组织抑制剂、胰岛素样生长因子的浓度来量化结合蛋白 7 和肾损伤分子 1 及其 AKI 严重程度（通过 48 小时血清定量）在 Aim 3 研究期间，使用潜变量回归模型观察肌酐相对于基线的变化。在肾 IR 损伤或假手术之前对小鼠施用 HDL 颗粒剂量，以及 HDL 的影响在第二个实验中，将对含有不同 miRNA 的 HDL 进行量化。在肾 IR 损伤前给药，以确定特定 HDL-miRNA 对 AKI 的影响。通过完成这项研究，史密斯博士将接受转化研究团队管理方面的培训，并 Linton 博士的体内实验设计；围手术期临床研究执行和 AKI 表型分析 Billings；以及 Vickers In 博士的 HDL 相关 microRNA (miRNA) 测序和生物信息学分析。以这种方式，在职业发展奖、她的导师团队和她的机构的支持下史密斯博士将获得建立独立转化研究所需的技能该计划的重点是开发基于脂蛋白的新型疗法以减少术后 AKI。