Perioperative high-density lipoprotein and postoperative AKI

项目总结-无变更 该奖项将支持一项前瞻性临床研究和Loren E的职业发展。Smith，MD，PhD， 并为她提供前瞻性临床研究所需的技能和经验，以推动她实现 她的长期目标是成为一个独立的翻译医生，科学家谁发现新的方法 围手术期肾脏保护，以减少急性肾损伤（阿基）。史密斯博士完成了高密度 与辛辛那提大学的Sean Davidson博士一起进行脂蛋白（HDL）分子生物学和住院医师培训 在麻醉学在范德比尔特大学医学中心（VUMC），在那里她被任命为教师在2017年。 VUMC是一家三级学术医院，以其高度合作的研究环境而闻名， 职业发展计划和广泛的核心设施。在她的T32奖学金期间，史密斯博士和她 导师林顿、比林斯和维克斯博士发现，术前高密度脂蛋白和高密度脂蛋白血症之间存在关联， 减少术后阿基。史密斯博士正在探索这种关联，以设计脂蛋白为基础的治疗方法 关于阿基通过完成这项研究，她将获得翻译研究团队管理方面的培训 林顿博士的围手术期临床研究执行和阿基表型分析， Billings，以及Vickers博士的尖端HDL相关microRNA（miRNA）测序和定量。 博士Smith将检验特定HDL蛋白和miRNA与术后阿基相关的假设 (Aim 1），并且HDL抗炎和抗氧化功能能力的增加与 阿基降低（Aim 2）。她将在一项150名受试者的前瞻性研究中检验这些假设， 心脏或血管手术。将在术前、术中和术后采集血液、尿液和临床数据。 将通过测量载脂蛋白A-I和血清淀粉样蛋白A来表征研究受试者的HDL组成 (SAA)蛋白质含量和测序HDL相关的miRNA。HDL的抗炎能力将 定量为HDL颗粒抑制SAA刺激的巨噬细胞IL-6和TNF-α表达的体外能力 抑制缺氧时肾近曲小管细胞TLR 2和TLR 4的表达。HDL对氧磷酶-1活性 将被用来估计抗氧化能力。这些HDL特征将与肾损害的严重程度进行比较。 肾小管应激和损伤，通过尿金属蛋白酶组织抑制剂2、胰岛素样 生长因子结合蛋白7和肾损伤分子1以及阿基的严重程度，用48小时定量 使用多变量回归模型进行血清肌酐较基线的变化，校正潜在 混杂因素。然后，将HDL性质和阿基之间确定的关联作为 术前HDL浓度与阿基之间的相关性。 在这个职业发展奖的支持下，她的导师团队，和她的机构环境，博士。 史密斯将获得建立转化研究计划所需的技能，以减少术后阿基。

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.