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

基本信息

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
项目类别：
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

项目摘要

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。该候选人目前是肯塔基大学药学院的助理教授。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。职业发展活动将使候选人具备成为一名独立临床和转化科学家对超过 400 万人进行以患者为导向的 SA-AKI 研究。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性护理和肾脏替代疗法。脓毒症会导致血管紧张素转换酶 (ACE) 和 ACE2 破坏，从而导致严重失调这种破坏可能最终导致局部过量的促炎性经典 RAS 和反调节、抗炎替代 RAS (Alt-RAS) 肾内 RAS 的缺陷，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 激活的替代标志物，使用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我们的中心假设是再生 RAS 或 Alt-RAS 的缺陷相对于 RAS 存在。 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，我们提出了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 缺乏的程度（相对于经典 RAS）与肾损伤的程度相对应，并且与本研究相一致的肾内 RAS 激活职业发展活动包括：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入门机器学习，以及学习 SA-AKI 的临床前模型。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。