Perioperative high-density lipoprotein and postoperative AKI

项目摘要--未更改 该奖项将支持罗兰·E·史密斯的一项前瞻性临床研究和职业发展， 并为她提供在前瞻性临床研究中所需的技能和经验，以推动她迈向 她的长期目标是成为一名发现新方法的独立翻译内科医生兼科学家 加强围手术期肾脏保护，减少急性肾损伤(AKI)。史密斯博士完成了高密度的博士学位 辛辛那提大学肖恩·戴维森博士的脂蛋白(高密度脂蛋白)分子生物学和住院医师培训 在范德比尔特大学医学中心(VUMC)学习麻醉学，2017年被任命为该校教员。 VUMC是一家以高度协作的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奖学金期间，史密斯博士和她的 Mentors，Linton，Billings和Vickers博士发现，较高的术前高密度脂蛋白和 术后AKI减少。史密斯博士正在探索这种联系，以便设计基于脂蛋白的治疗方法。 为了AKI。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 以及Linton博士的高密度脂蛋白功能分析、围手术期临床研究执行情况和Dr. 以及来自Vickers博士的尖端高密度脂蛋白相关微RNA(MiRNA)测序和定量。 史密斯博士将检验特定的高密度脂蛋白和miRNA与术后AKI相关的假说 (目标1)，高密度脂蛋白抗炎和抗氧化功能的增强与 减少AKI(目标2)。她将在一项对150名患者进行的前瞻性研究中检验这些假设。 心脏或血管外科手术。将在手术前、手术中和手术后收集血液、尿液和临床数据。 研究对象的高密度脂蛋白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)蛋白质含量和对高密度脂蛋白相关miRNAs的测序。高密度脂蛋白的抗炎能力将 高密度脂蛋白颗粒体外抑制沙门冬氨酸刺激的巨噬细胞IL-6和肿瘤坏死因子-α表达的能力 抑制低氧时肾小管上皮细胞TLR2和TL4的表达。高密度脂蛋白对氧磷酶-1活性 将被用来估计抗氧化能力。这些高密度脂蛋白的特征将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组织抑制因子2、胰岛素样物质的水平来量化 生长因子结合蛋白7、肾损伤分子1和AKI严重程度的关系，用48小时定量 基于潜力调整的多元回归模型对基线后血清肌酐变化的研究 混血儿。确定的高密度脂蛋白特性和AKI之间的关联将作为 术前高密度脂蛋白浓度与AKI的关系 在这个职业发展奖的支持下，她的导师团队和她所处的机构环境。 史密斯将获得建立翻译研究计划以减少术后AKI所需的技能。

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.