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

脓毒症相关 AKI 中的经典和替代肾素-血管紧张素系统失调：逆向翻译方法

• 批准号: 10536651
• 负责人: Alexander H Flannery
• 金额: $ 15.76万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10536651
• 关键词: ACE2; Acute; Acute Renal Failure with Renal Papillary Necrosis; Angiotensin II; Angiotensinogen; Angiotensins; Anti-Inflammatory Agents; Biological Assay; Biological Markers; Chronic; Chronic Disease; Classification; Clinical; Clinical Research; Critical Illness; Data; Development; End stage renal failure; Etiology; Event; Evolution; Frequencies; Functional disorder; Future; Health; Hospitalization; Infection; Inflammatory; Injury; Injury to Kidney; Kentucky; Kidney; Laboratories; Learning; Machine Learning; Mass Spectrum Analysis; Measurement; Measures; Mentorship; Mission; Modeling; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; Outcome; Patient-Focused Outcomes; Patients; Peptides; Peptidyl-Dipeptidase A; Pharmacy facility; Pre-Clinical Model; Program Development; Prospective cohort; Proteins; Public Health; Quality of life; Recovery; Renal Replacement Therapy; Renin; Renin-Angiotensin System; Research; Research Personnel; Risk; Risk Marker; Role; Sepsis; Septic Shock; Statistical Data Interpretation; Supportive care; Surrogate Markers; Testing; Therapeutic; Tissues; Training; Translational Research; Tubular formation; Universities; Up-Regulation; Urine; bench to bedside; biobank; career development; clinical care; clinical translation; cohort; college; complex biological systems; improved; metabolome; metabolomics; molecular marker; mortality; mouse model; patient oriented research; patient subsets; professor; receptor; receptor expression; regenerative; renal damage; response; skills; translational approach; translational model; translational scientist; urinary

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.

项目摘要/摘要 该建议包括一项五年研究职业发展计划，以研究经典和替代方案 败血症相关的急性肾脏损伤（SA-AKI）中的肾素 - 血管紧张素系统（RAS）失调。这 候选人目前是肯塔基大学药学院的助理教授。提案 建立在候选人在AKI临床研究中的强大背景，并整合了来自 Sa-Aki的败血症，AKI，RAS疗法和鼠模型的成立研究者。提议 职业发展活动将使候选人掌握成为必要的技能 独立的临床和翻译科学家对SA-AKI进行以患者为导向的研究。超过400万 患者每年用AKI住院，败血症估计会造成所有病例的26-50％。 当前的疗法仅限于支持性护理和肾脏替代疗法。最近的证据表明 败血症会导致血管紧张素转化酶（ACE）和ACE2的破坏，可能严重失调 拉斯。这种破坏最终可能导致局部超过促炎，经典的Ras和 反调节性，抗炎替代性RA（ALT-RAS）的缺陷。肾脏内拉斯， 独立于电路RAS运行，可能会驱动病理生理学和尿RAS生物标志物 已被认为是肾脏内RAS激活的替代标记。使用床头到基础的方法， 我们的总体目标是量化电路和组织上存在的经典和Alt-Ras灾难 Sa-Aki的水平，并评估这场灾难程度与主要不良肾脏之间的关系 事件。我们的核心假设是，相对于该再生Ras或Alt-Ras的缺乏 在电路和组织水平的Sa-Aki中的经典RAS，并且这种不平衡的程度有所不同 与SA-AKI患者的结果相关联。我们提出了三个特定目标来实现这一目标：（1） 确定RAS失调，管状损伤和功能的肾脏生物标志物之间的关系，以及 在Sa-Aki的30天内（Make-30）内进行重大不良肾脏事件，（2）评估 肾内RAS激活的尿生物标志物，并在重症患者中使结局达到一年 使用Sa-Aki和异源AKI，以及（3）测试肾脏Ras辣椒代谢组的假设 在Sa-Aki的鼠模型中，受体表达概况转移到再生或Alt-Ras缺乏症，以及 Alt-Ras缺乏症（相对于经典RA）的程度对应于肾脏损伤的程度和 肾脏内RAS激活。与这项研究保持一致的职业发展活动包括：培训 应用实验室测定法，包括质谱，统计分析技能的提高 纵向数据和简介机器学习，并学习SA-AKI的临床前模型。这个建议 通过进一步理解萨阿基（Aki）和肾脏的主要原因来支持NIDDK的任务 影响公众健康和生活质量的并发症。