Perioperative high-density lipoprotein and postoperative AKI

围手术期高密度脂蛋白与术后 AKI

基本信息

批准号：
10280853
负责人：
Loren Elisa Smith
金额：
$ 3万
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/10280853
关键词：
Academic Medical Centers Activities of Daily Living Acute Renal Failure with Renal Papillary Necrosis Affect Anesthesiology Anti-Inflammatory Agents Antioxidants Apolipoprotein A-I Arylesterase Award 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 Endothelium Environment Enzyme-Linked Immunosorbent Assay F2-Isoprostanes Faculty Fellowship Free Radicals Goals High Density Lipoproteins Hospitals Hour Human Hypoxia In Vitro Incubated Injury to Kidney Intercellular adhesion molecule 1 Interleukin-6 K-Series Research Career Programs Kidney Lecithin Lipid Peroxidation Lipoproteins Measurement Measures Mediating Mediator of activation protein Mentors Mentorship Methods MicroRNAs Modeling Molecular Biology Mus Neutrophil Infiltration Operative Surgical Procedures Outcome Oxidants Oxidative Stress Patients Perioperative Pharmacology Phenotype Plasma Postoperative Period Program Development Property Prospective Studies Proteins Proximal Kidney Tubules Rattus Renal tubule structure Reperfusion Injury Reperfusion Therapy Research Residencies Risk Scientist Serum Serum amyloid A protein 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 development design experience injury prevention insulin-like growth factor binding protein-related protein 1 macrophage miRNA expression profiling novel particle prevent prospective rat KIM-1 protein recruit renal damage renal ischemia sham surgery skills translational physician translational research program urinary

项目摘要

PROJECT SUMMARY- NO CHANGE This award will support a prospective clinical study and the career development of Loren E. Smith, MD, PhD, and provide her with the skills and experience in prospective clinical research needed to advance her towards her long-term goal of becoming an independent translational physician-scientist who discovers novel methods of perioperative renal protection to decrease acute kidney injury (AKI). 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 postoperative AKI. Dr. Smith is exploring this association in order to design lipoprotein-based treatments for AKI. By completing this study, she will obtain training in the management of a translational research team and HDL functional analysis from Dr. Linton, perioperative clinical study execution and AKI phenotyping from Dr. Billings, and cutting-edge HDL-associated microRNA (miRNA) sequencing and quantification from Dr. Vickers. Dr. Smith will test the hypotheses that specific HDL proteins and miRNA are associated with postoperative AKI (Aim 1), and that increased HDL anti-inflammatory and anti-oxidant functional capacities are associated with decreased AKI (Aim 2). She will test these hypotheses in a 150-subject prospective study of patients undergoing cardiac or vascular surgery. Blood, urine, and clinical data will be collected prior to, during, and following surgery. Study subject's HDL composition will be characterized by measuring apolipoprotein A-I and serum amyloid A (SAA) protein content and by sequencing HDL-associated miRNAs. HDL anti-inflammatory capacity will be quantified as HDL particles' in vitro capacity to suppress SAA-stimulated macrophage IL-6 and TNF-α expression and to suppress renal proximal tubule cell TLR2 and 4 expression during hypoxia. HDL paraoxonase-1 activity will be used to estimate anti-oxidant capacity. These HDL characteristics will be compared to severity of renal tubule stress and damage, quantified by urinary levels of tissue inhibitor of metalloproteinase 2, insulin-like growth factor-binding protein 7, and kidney injury molecule 1 and to severity of AKI, quantified with 48-hour serum creatinine change from baseline using multivariate regression modeling, adjusted for potential confounders. Associations identified between HDL properties and AKI will then be evaluated as mediators of the association between preoperative HDL concentration and AKI. With the support of this career development award, her mentorship team, and her institutional environment, Dr. Smith will gain the skills required to establish a translational research program to reduce postoperative AKI.

项目摘要 - 没有变化该奖项将支持 Loren E. Smith 医学博士、哲学博士的前瞻性临床研究和职业发展并为她提供前瞻性临床研究所需的技能和经验，以推动她走向成功她的长期目标是成为一名发现新方法的独立转化医学科学家 Smith 博士完成了高密度领域的博士学位。辛辛那提大学 Sean Davidson 博士的脂蛋白 (HDL) 分子生物学和住院医师培训她在范德比尔特大学医学中心 (VUMC) 获得麻醉学博士学位，并于 2017 年被任命为该中心的教员。 VUMC 是一家三级学术医院，以其高度协作的研究环境、卓越的环境而闻名。史密斯博士和她在 T32 奖学金期间获得了职业发展计划和广泛的核心设施。导师 Linton、Billings 和 Vickers 博士发现，术前高密度脂蛋白 (HDL) 与 Smith 博士正在探索这种关联，以设计基于脂蛋白的治疗方法。通过完成这项研究，她将获得转化研究团队管理方面的培训。 Linton 博士提供的 HDL 功能分析、围术期临床研究执行和 AKI 表型分析来自 Linton 博士。 Billings 和 Vickers 博士提供的尖端 HDL 相关 microRNA (miRNA) 测序和定量技术。 Smith 博士将测试特定 HDL 蛋白和 miRNA 与术后 AKI 相关的假设（目标 1），HDL 抗炎和抗氧化功能能力的增加与她将在一项 150 名接受过 AKI 治疗的患者的前瞻性研究中检验这些假设。心脏或血管手术将在手术前、手术中和手术后收集血液、尿液和临床数据。研究对象的 HDL 组成将通过测量载脂蛋白 A-I 和血清淀粉样蛋白 A 来表征 (SAA) 蛋白质含量并通过对 HDL 相关 miRNA 进行测序来了解 HDL 抗炎能力。量化为 HDL 颗粒体外抑制 SAA 刺激的巨噬细胞 IL-6 和 TNF-α 表达的能力并在缺氧期间抑制近曲小管细胞 TLR2 和 4 的表达。将用于估计抗氧化能力，并将这些 HDL 特征与肾脏的严重程度进行比较。肾小管应激和损伤，通过尿液中金属蛋白酶 2 组织抑制剂（胰岛素样）水平进行量化生长因子结合蛋白 7 和肾损伤分子 1 以及 AKI 的严重程度（48 小时定量）使用多元回归模型计算血清肌酐相对于基线的变化，并根据潜力进行调整 HDL 特性和 AKI 之间的混杂因素将被评估为中介因素。术前 HDL 浓度与 AKI 之间的关系。在这个职业发展奖、她的导师团队和她的机构环境的支持下，博士。史密斯将获得建立转化研究计划以减少术后 AKI 所需的技能。