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 - 没有更改该奖项将支持一项前瞻性临床研究和洛伦·E·史密斯（Loren E. Smith）博士的职业发展并为她提供前瞻性临床研究的技能和经验，以使她朝着她成为独立翻译的身体科学家的长期目标，发现了新方法定期肾脏保护以减少急性肾脏损伤（AKI）。史密斯博士完成了高密度的博士学位辛辛那提大学和居住培训的Sean Davidson博士脂蛋白（HDL）分子生物学范德比尔特大学医学中心（VUMC）的麻醉学，2017年被任命为教职员工。 VUMC是一家以其高度协作研究环境而闻名的三级学术医院职业发展计划和广泛的核心设施。在她的T32奖学金中，史密斯博士和她导师，博士。 Linton，Billings和Vickers发现了较高的术前HDL和减少了术后AKI。史密斯博士正在探索这种关联，以设计基于脂蛋白的治疗方法对于Aki。通过完成这项研究，她将获得转化研究团队管理的培训 Linton博士的HDL功能分析，定期临床研究执行和AKI表型。账单和尖端的HDL相关microRNA（miRNA）测序和Vickers博士的定量。史密斯博士将测试特定的HDL蛋白和miRNA与术后AKI有关的假设（AIM 1），而HDL抗炎和抗氧化功能能力增加与减少了AKI（AIM 2）。她将在接受正在进行的患者的150个受试者的前瞻性研究中检验这些假设心脏或血管手术。在手术之前，期间和之后，将收集血液，尿液和临床数据。研究对象的HDL组成将以测量载脂蛋白A-I和血清淀粉样蛋白A的特征（SAA）蛋白质含量和测序与HDL相关的miRNA。 HDL抗炎能力将是量化为HDL颗粒的体外能力，以抑制SAA刺激的巨噬细胞IL-6和TNF-α表达并抑制缺氧期间肾近端细胞TLR2和4表达。 HDL二氧酮酶-1活性将用于估计抗氧化能力。这些HDL特征将与肾脏的严重程度进行比较小管应激和损伤，由金属蛋白酶2的组织抑制剂的尿液水平定量，胰岛素样生长因子结合蛋白7和肾损伤分子1和AKI的严重程度，用48小时定量血清肌酐使用多元回归建模从基线变化，调整了潜力混淆者。然后将评估HDL属性和AKI之间确定的关联术前HDL浓度与AKI之间的关联。在这一职业发展奖的支持下，她的Mentalship团队以及她的机构环境博士史密斯将获得建立翻译研究计划所需的技能，以减少术后AKI。