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: 10369811
• 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/10369811
• 关键词: ACE2; Acute; Acute Renal Failure with Renal Papillary Necrosis; Angiotensin II; Angiotensinogen; Angiotensins; Anti-Inflammatory Agents; Biological Assay; Biological Markers; Cecum; Chronic Disease; Chronic Kidney Failure; Classification; Clinical; Clinical Research; Critical Illness; Data; Development; End stage renal failure; Etiology; Event; Evolution; Frequencies; Functional disorder; Future; Health; Infection; 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; Translations; Tubular formation; Universities; Up-Regulation; Urine; bench to bedside; biobank; career development; clinical care; 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 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.

项目概要/摘要 该提案包括一个为期五年的研究职业发展计划，以研究古典和另类 脓毒症相关急性肾损伤（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 以候选人在 AKI 临床研究方面的强大背景为基础，并整合了来自 在脓毒症、AKI、RAS 治疗和 SA-AKI 小鼠模型方面建立了研究人员。拟议的 职业发展活动将使候选人具备成为一名成功人士所需的技能 独立的临床和转化科学家，对 SA-AKI 进行以患者为导向的研究。超过400万 每年都有患者因 AKI 住院，脓毒症估计占所有病例的 26-50%。 目前的治疗仅限于支持治疗和肾脏替代疗法。最近的证据表明 脓毒症会导致血管紧张素转换酶 (ACE) 和 ACE2 破坏，从而导致严重失调 RAS。这种破坏可能最终导致局部过量的促炎、经典 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液 RAS 生物标志物 已被提议作为肾内 RAS 激活的替代标记。采用从床边到工作台的方法， 我们的总体目标是量化循环系统和组织中存在的经典和 Alt-RAS 干扰 SA-AKI 水平，并评估这种紊乱的程度与主要肾脏不良之间的关系 事件。我们的中心假设是再生 RAS 或 Alt-RAS 的缺陷相对于 SA-AKI 中的经典 RAS 在循环和组织水平上存在差异，并且这种不平衡的程度存在差异 与 SA-AKI 患者的预后相关。我们提出三个具体目标来实现这一目标：（1） 确定 RAS 失调、肾小管损伤和功能的肾脏生物标志物之间的关系，以及 SA-AKI 中 30 天内主要肾脏不良事件 (MAKE-30)，(2) 评估之间的关系 肾内 RAS 激活的尿液生物标志物以及危重患者一年内的预后结果 与 SA-AKI 和异源 AKI，以及 (3) 检验肾脏 RAS 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或 Alt-RAS 缺陷，并且 Alt-RAS 缺陷的程度（相对于经典 RAS）与肾损伤的程度相对应，并且 肾内 RAS 激活。与本研究相符的职业发展活动包括： 实验室分析的应用，包括质谱分析、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。这个提议 通过进一步了解 SA-AKI（AKI 和肾脏的主要原因）来支持 NIDDK 的使命 影响公众健康和生活质量的并发症。