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.

项目总结/摘要 这项建议包括一个为期五年的研究职业发展计划，学习古典和另类 脓毒症相关急性肾损伤（SA-AKI）中的肾素-血管紧张素系统（RAS）失调。的 候选人目前是肯塔基州大学药学院的助理教授。该提案 基于候选人在阿基临床研究方面的强大背景， 在脓毒症、阿基、RAS治疗和SA-AKI的鼠模型中建立了研究者。拟议 职业发展活动将使候选人具备必要的技能，以成为一个 独立的临床和转化科学家，对SA-AKI进行面向患者的研究。超过4百万 每年都有患者因阿基住院，估计脓毒症占所有病例的26-50%。 目前的治疗仅限于支持性治疗和肾脏替代治疗。最近的证据表明 脓毒症导致血管紧张素转换酶（ACE）和ACE 2的破坏， RAS。这种破坏可能最终导致局部过量的促炎性、经典的RAS， 在反调节，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生物标志物 已被提议作为肾内RAS激活的替代标志物。采用从床边到长凳的方法， 我们的总体目标是量化存在于循环和组织中的经典和Alt-RAS紊乱， 水平，并评估这种紊乱的程度与主要不良肾损伤之间的关系。 事件我们的中心假设是，再生RAS或Alt-RAS的缺陷相对于 经典RAS在SA-AKI中在循环和组织水平，这种不平衡的程度差异 与SA-AKI患者的结局相关。为此，我们提出三个具体目标：（1） 确定RAS失调、肾小管损伤和功能的肾脏生物标志物之间的关系，以及 SA-AKI患者30天内的主要肾脏不良事件（MAKE-30），（2）评估 危重患者肾内RAS激活的尿生物标志物和1年内MAKE结局 与SA-AKI和异质性阿基，和（3）为了测试假设，肾RAS肽代谢组 并且受体表达谱在SA-AKI的鼠模型中转变为再生或Alt-RAS缺陷，以及 Alt-RAS缺陷的程度（相对于经典RAS）与肾损伤的程度相对应， 肾内RAS激活。与本研究相一致的职业发展活动包括： 实验室分析的应用，包括质谱法，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 支持NIDDK的使命，进一步了解SA-阿基，这是阿基和肾脏的主要原因 影响公众健康和生活质量的并发症。