Monitoring pro-resolving leukocyte responses in peripheral blood predicts clinical severity during sepsis

监测外周血中促溶解白细胞反应可预测脓毒症期间的临床严重程度

基本信息

批准号：
10354958
负责人：
Bruce D Levy
金额：
$ 23.78万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
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 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10354958
关键词：
Address Affect Agonist Anti-Inflammatory Agents Biological Assay Biological Models Blood Blood Volume Blood capillaries Blood specimen Cause of Death Cells Cessation of life Clinical Clinical Data Clinical Management Clinical assessments Collection Communities Critical Care Critical Illness Data Data Set Defect Devices Diagnostic Disease Disease Progression Experimental Models Family Flow Cytometry Functional disorder Future Generations Goals Health Homeostasis Hospitals Human Immune Immune response Infection Inflammation Inflammatory Inflammatory Response Integration Host Factors Intervention Studies Length of Stay Leukocytes Link Logistics Maps Mass Spectrum Analysis Measures Mediating Mediator of activation protein Methodology Microfluidics Modeling Molecular Monitor Mus National Institute of General Medical Sciences Organ Organ failure Pathway interactions Patient Rights Patient-Focused Outcomes Patients Peripheral Phagolysosome Phase Phenotype Phosphorylation Population Process Protein Analysis Proteomics Recovery Registries Reproducibility Research Resolution Risk Sampling Sepsis Severities Shock Signal Pathway Signal Transduction Stratification System Technology Testing Time Tissues Transition Elements Venous White Blood Cell Count procedure Whole Blood Work base biobank cell type cellular transduction clinical biomarkers clinical predictors clinical prognostic counterregulation design immune function improved innovation leukocyte activation longitudinal analysis mortality neutrophil new therapeutic target novel novel therapeutic intervention organ injury patient health information patient subsets peripheral blood phosphoproteomics prognostic prognostic indicator protein expression receptor response restoration scale up septic patients

项目摘要

Abstract Sepsis is characterized by immune cell dysfunction, which is linked to the pathophysiology of the disease with consequent organ injury and increased associated mortality. In experimental sepsis in mice, regulating leukocyte function decreases organ injury and lessens the severity of the infection. Assessment of peripheral blood leukocyte activation and function may serve as prognostic clinical biomarkers and inform new therapeutic strategies for the management of human sepsis and inflammatory diseases. Resolution of inflammation is an active process with anti-inflammatory and pro-resolving mechanisms. There are several families of resolution mediators, termed “specialized pro-resolving mediators (SPMs)”, that serve as agonists at cognate receptors to transduce cell-type specific responses on leukocytes and in experimental model systems these SPMs decrease the severity and duration of sepsis. Recently, in microliter quantities of peripheral blood, we determined that functional characterization of leukocyte responses was more informative than leukocyte counting for clinical assessment of the trajectory of critical illness. In response to the NIGMS NOT-GM-19-054 “Exploring the Scientific Value of Existing or New Sepsis Human Biospecimen Collections”, the proposed proof of concept and scale-up studies are designed to determine the scientific value of our existing and ongoing Registry of Critical Illness biorepository of human sepsis biospecimens with associated patient health record data. These biospecimens are collected at presentation, hospital day 3 and hospital 7 to align with the clinical trajectory of the patient, linked to clinical datasets and represent transformative potential for sepsis endotyping/stratification. Here, we propose the use of isodielectric separation as a contemporary cutting-edge technology in the analysis of these biospecimens to uncover leukocyte activation during the upslope and resolution of patient’s immune responses that will test the hypothesis: Sepsis hyper- inflammatory responses result from defective endogenous resolution mechanisms and that these defects are evident in peripheral blood leukocyte activation and functional responses to SPMs. To address this hypothesis, we plan four specific aims. In the R21 phase, (1) demonstrate reproducible isolation and functional analysis of neutrophils from capillary blood, and (2) demonstrate ability to obtain deep proteomic and phosphoproteomic profiles from small numbers of neutrophils. In the R33 phase, (3) longitudinal analysis of SPM pathway activation during sepsis resolution, and (4) inference and model generation and testing with ex vivo assays. The goals of this application are to develop an improved understanding of the resolution defects that unleash unrestrained inflammation of sepsis with a longer term goal for new therapeutic targets and prognostic indicators of disease progression. Important products of this application include provision of guidance on the best practices for collecting, utilizing, and analyzing human biospecimens to maximize their value for the entire sepsis research community.

抽象的败血症的特征是免疫细胞功能障碍，该功能与该疾病的病理生理有关随之而来的器官损伤并增加了相关的死亡率。在小鼠的实验性败血症中，调节白细胞功能会降低器官损伤并降低感染的严重程度。外围评估血清细胞激活和功能可能是预后的临床生物标志物，并告知新的治疗人类败血症和炎症性疾病的治疗策略。解决方案炎症是一种具有抗炎和促疾病机制的活跃过程。有几个分辨率调解员的家庭被称为“专门的支持促进调解人（SPM）”，作为激动剂的家族在同源受体上，以翻译白细胞和实验模型的细胞类型特异性反应系统这些SPM降低了败血症的严重程度和持续时间。最近，以微晶数量的数量外围血，我们确定白细胞反应的功能表征更有信息比白细胞计算重症疾病轨迹的临床评估。响应裸体 Not-GM-19-054“探索现有或新败血症的人类生物传感收集的科学价值”，拟议的概念证明和扩大研究旨在确定我们的科学价值人类败血症生物测量生物术的现有和正在进行的注册表与相关的患者健康记录数据。这些生物测量是在介绍，医院第3天和医院第7期收集到的与患者的临床轨迹保持一致，与临床数据集有关并表示变革潜力用于败血症内型/分层。在这里，我们建议将等型分离用作当代在分析这些生物测量以发现白细胞激活期间的尖端技术上坡和解决患者的免疫反应的分辨率将检验假设：败血症高 - 炎症反应是由于内源性分辨率有缺陷而导致的，外周血白细胞激活和对SPM的功能反应证明了缺陷。为了解决这一假设，我们计划了四个具体目标。在R21阶段，（1）证明可再现毛细血管血液中嗜中性粒细胞的分离和功能分析，（2）证明能够获得深来自少数嗜中性粒细胞的蛋白质组学和磷酸蛋白质组学特征。在R33阶段，（3）纵向分析败血症过程中SPM途径激活的分析，（4）推断和模型产生和通过体内测定进行测试。该应用的目标是对解决方案缺陷，释放了败血症的不受约束的炎症，并具有长期目标的新疗法疾病进展的目标和预后指标。此应用的重要产品包括提供有关收集，使用和分析人类生物测量的最佳实践指南最大化其对整个败血症研究社区的价值。