Classical and Alternative Renin-Angiotensin System Dysregulation in Sepsis-Associated AKI: A Reverse Translation Approach

项目摘要/摘要 这项提议包括一项为期五年的研究职业发展计划，学习古典和另类 脓毒症相关性急性肾损伤(SA-AKI)的肾素-血管紧张素系统(RAS)失调这个 候选人目前是肯塔基大学药学院的助理教授。这项建议 基于候选人在AKI临床研究方面的强大背景，并整合了以下方面的指导 在脓毒症、AKI、RAS疗法和SA-AKI小鼠模型方面的成熟研究人员。建议数 职业发展活动将使应聘者具备成为一名 独立的临床和翻译科学家，从事以患者为中心的SA-AKI研究。400多万 每年都有患者因AKI住院，据估计，败血症占所有病例的26%-50%。 目前的治疗方法仅限于支持性护理和肾脏替代疗法。最近的证据表明 脓毒症导致血管紧张素转换酶(ACE)和血管紧张素转换酶(ACE2)紊乱，可能导致严重的调节失调 RAS。这种破坏最终可能导致局部过度的促炎性、经典的RAS和 反调节、抗炎替代RAS(Alt-RAS)的缺陷。肾内RAS， 独立于循环RAS运行，可能驱动病理生理学和尿RAS生物标记物 已被认为是肾内RAS激活的替代标志物。使用床边到长椅的方法， 我们的总体目标是量化循环和组织中存在的经典和Alt-RAS干扰 SA-AKI水平，并评价这种紊乱的程度与主要不良肾脏的关系 事件。我们的中心假设是再生RAS或Alt-RAS的缺陷相对于 循环和组织水平SA-AKI中的经典RAS，这种失衡的程度不同 与SA-AKI患者的预后相关。为此，我们提出三个具体目标：(1) 确定RAS失调、肾小管损伤的生物标志物和功能之间的关系 30天内主要不良肾脏事件(Make-30)在SA-AKI中，(2)评估 危重病患者肾内RAS活性和一年预后的尿液生物标志物 用SA-AKI和异源AKI，以及(3)检验肾脏RAS多肽代谢组的假设 在SA-AKI小鼠模型中，受体表达谱转变为再生性或Alt-RAS缺乏症，并且 Alt-RAS缺乏的程度(相对于经典RAS)与肾脏损伤的程度和 肾内RAS激活。符合这项研究的职业发展活动包括：培训 包括质谱学在内的实验室分析的应用，统计分析技能的进步 纵向数据和介绍性机器学习，以及学习SA-AKI的临床前模型。这项建议 通过加深对SA-AKI的了解，支持NIDDK的使命，SA-AKI是AKI和肾脏的主要事业 影响公众健康和生活质量的并发症。

PROJECT SUMMARY/ABSTRACT This proposal includes a five-year research career development program to study classical and alternative renin-angiotensin system (RAS) dysregulation in sepsis-associated acute kidney injury (SA-AKI). The candidate is currently an Assistant Professor at the University of Kentucky College of Pharmacy. The proposal builds on the candidate’s strong background in clinical research on AKI and integrates mentorship from established investigators in sepsis, AKI, RAS therapeutics, and murine models of SA-AKI. The proposed career development activities will equip the candidate with the skills necessary to become established as an independent clinical and translational scientist conducting patient-oriented research on SA-AKI. Over 4 million patients are hospitalized annually with AKI, and sepsis is estimated to contribute to 26-50% of all cases. Current therapy is limited to supportive care and kidney replacement therapy. Recent evidence suggests sepsis causes a disruption in angiotensin converting enzyme (ACE) and ACE2 that could severely dysregulate the RAS. This disruption may ultimately result in local excess of the proinflammatory, classical RAS and deficiencies in the counter-regulatory, anti-inflammatory alternative RAS (Alt-RAS). An intra-renal RAS, operating independently from the circulatory RAS, may drive pathophysiology and urinary RAS biomarkers have been proposed as surrogate markers of intra-renal RAS activation. Using a bedside-to-bench approach, our overall objective is to quantify the classical and Alt-RAS disturbances present at the circulatory and tissue level in SA-AKI, and evaluate the relationship between the extent of this disturbance and major adverse kidney events. Our central hypothesis is that a deficiency of the regenerative RAS, or Alt-RAS, exists relative to the classical RAS in SA-AKI at the circulatory and tissue level, and that the degree of this imbalance differentially associates with outcomes in patients with SA-AKI. We propose three specific aims to accomplish this: (1) To determine the relationship between RAS dysregulation, kidney biomarkers of tubular injury and function, and major adverse kidney events within 30 days (MAKE-30) in SA-AKI, (2) To assess the relationship between urinary biomarkers of intra-renal RAS activation and MAKE outcomes out to one year in critically ill patients with SA-AKI and heterogenous AKI, and (3) To test the hypothesis that the kidney RAS peptide metabolome and receptor expression profile shift to a regenerative or Alt-RAS deficiency in a murine model of SA-AKI, and that the degree of Alt-RAS deficiency (relative to classical RAS) corresponds to the degree of kidney injury and intra-renal RAS activation. Career development activities that align with this research include: training in application of laboratory assays including mass spectrometry, advancement of statistical analysis skills with longitudinal data and introductory machine learning, and learning pre-clinical models of SA-AKI. This proposal supports the mission of NIDDK by furthering the understanding of SA- AKI, a leading cause of AKI and kidney complications impacting the public’s health and quality of life.