Cellular and Metabolic Dysfunction in Sepsis-Induced Immune Paralysis

脓毒症引起的免疫麻痹中的细胞和代谢功能障碍

• 批准号: 10724018
• 负责人: Lisa Kristina Torres
• 金额: $ 19.6万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10724018
• 关键词: Address; Admission activity; Agonist; Anti-Inflammatory Agents; Antibodies; Binding; Biological; Biological Assay; Biological Markers; Biology; Body Fluids; CD14 gene; Carnitine; Catabolism; Cell Line; Cells; Cellular Metabolic Process; Cessation of life; Characteristics; Clinical; Clinical Pathways; Clinical Trials; Collection; Complex; Critical Illness; Critical Pathways; Data; Disease; Energy Metabolism; Energy Metabolism Pathway; Enrollment; Enzyme-Linked Immunosorbent Assay; Evaluation; Exhibits; Fatty Acids; Functional disorder; Future; Glycolysis; Goals; HLA-DR Antigens; Hospitals; Hour; Immune; Immune Targeting; Immune Tolerance; Immune response; Immune signaling; Immunoassay; Immunosuppression; Impairment; Inflammation; Influentials; Intervention; K-Series Research Career Programs; Label; Leukocytes; Link; Long-Term Effects; Measures; Mediating; Mediation; Mediator; Mentors; Metabolic; Metabolic dysfunction; Metabolism; Methods; Mitochondria; Molecular Epidemiology; Morbidity - disease rate; Observational Study; Outcome; Oxidative Phosphorylation; Paralysed; Pathogenesis; Pathologic; Pathway interactions; Patient Recruitments; Patient-Focused Outcomes; Patients; Performance; Peripheral Blood Mononuclear Cell; Plasma; Play; Predisposition; Proteins; Proteomics; Research; Research Design; Research Personnel; Role; Secondary to; Sepsis; Serum; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Signaling Molecule; Signaling Protein; Specimen; Statistical Data Interpretation; Structure; Supportive care; Surrogate Markers; Testing; Therapeutic Intervention; Training; Translational Research; Vial device; Whole Blood; adverse outcome; biobank; biomarker identification; candidate marker; candidate validation; career; clinically relevant; cohort; cytokine; design; experience; fatty acid metabolism; fatty acid oxidation; high risk; immune activation; immunosuppressed; improved; metabolomics; monocyte; mortality; multidisciplinary; opportunistic pathogen; pharmacologic; prospective; protein biomarkers; recruit; response; secondary infection; septic; septic patients; skills; success

PROJECT SUMMARY Sepsis-induced immune paralysis (IP) is associated with consequential and often long-term effects including susceptibility to secondary and opportunistic pathogens, and persistent immune disturbances that may culminate in low-grade inflammation and death. Alterations in immune cell metabolism and impaired cell signaling are pathophysiologic features of sepsis-induced IP. There is a strong scientific premise supporting the influential role of fatty acids (FA) and their acyl carnitine (AC) metabolites in cellular energy metabolism, immune signaling, and modulation of cytokine release. These concepts highlight the potential role of metabolites as active contributors to disease pathophysiology rather than solely representing consequences of underlying pathways. To address this paradigm, Lisa Torres, MD, MS, proposes this career development award with the overall objective to characterize metabolic and protein biomarkers of septic IP relative to the most widely accepted surrogate biomarker of IP, CD14+ monocyte HLA-DR expression. With the assistance of a multi-disciplinary mentoring team, Dr. Torres proposes the following Aims in a cohort of critically septic and non-septic patients, stratified by presence or absence of IP: (1) determine the relationship between dysregulated FA metabolism and sepsis-induced IP; (2) characterize the role of immune paralyzed response proteins (IPRPs) as cellular mediators and candidate biomarkers associated with sepsis-induced IP; and (3) explore the effect of IP as a mediating variable between sepsis and patient outcomes. In Aim 1, Dr. Torres will measure fatty acid oxidation (FAO) utilization and perform metabolic tracing with 13C-FAs to assess AC synthesis in PBMCs from recruited patients (N=280). In Aim 2, Dr. Torres will use a THP-1 monocyte-like cell line and patient PBMCs (Aim 1) to determine the impact of IPRP agonists on cellular activation. She will also measure IPRPs in plasma of recruited patients (Aim 1). In Aim 3, Dr. Torres will use causal inference methods to estimate the effect of IP as a mediator on the causal pathway between sepsis and adverse patient outcomes. Dr. Torres's long-term career goal is to become an independent researcher in sepsis translational investigation and molecular epidemiology, engaged in understanding endotypes and mechanisms that drive pathogenesis amongst critically ill patients. In this career development award, her goals are to gain focused training in FA metabolism; become proficient in immune cell signaling pathways of inflammation and inhibition of activation; develop skills to design, recruit and retain a cohort of critically ill subjects to explore the clinical relevance of patient characteristics and sepsis-induced IP on outcomes using causal inference methods; and build expertise in statistical analysis of complex biological data. She will accomplish this through mentoring, coursework, dissemination of research, and hands-on-experience, all necessary for her future success.

项目摘要 败血症引起的免疫麻痹（IP）与后果和长期影响有关 对继发性病原体和机会性病原体的敏感性以及可能达到顶峰的持续性免疫障碍 在低级炎症和死亡中。免疫细胞代谢和细胞信号受损的改变是 败血症引起的IP的病理生理特征。有一个强大的科学前提来支持有影响力的角色 细胞能量代谢，免疫信号传导和 细胞因子释放的调节。这些概念突出了代谢物作为活跃贡献者的潜在作用 疾病的病理生理学，而不是仅代表潜在途径的后果。解决 这个范式，马里兰州丽莎·托雷斯（Lisa Torres） 与最广泛接受的替代生物标志物相对于脓毒症IP的代谢和蛋白质生物标志物的特征 IP，CD14+单核细胞HLA-DR表达。在多学科指导团队的协助下 托雷斯（Torres 或IP的缺失：（1）确定FA代谢失调与败血症诱导的IP之间的关系； （2）将免疫瘫痪的反应蛋白（IPRP）作为细胞介质和候选者的作用 与败血症引起的IP相关的生物标志物； （3）探索IP作为中介变量的效果 败血症和患者结局。在AIM 1中，托雷斯博士将测量脂肪酸氧化（FAO）利用并进行 用13C-FAS进行代谢追踪，以评估招募患者的PBMC中的AC合成（n = 280）。在AIM 2中，博士 托雷斯将使用THP-1单核细胞状细胞系和患者PBMC（AIM 1）来确定IPRP的影响 激动剂对细胞激活。她还将在招募患者的血浆中测量IPRP（AIM 1）。在AIM 3中， 托雷斯博士将使用因果推理方法来估计IP作为因果途径的介体的影响 在败血症和不良患者结局之间。托雷斯博士的长期职业目标是成为独立 败血症转化研究和分子流行病学的研究人员从事理解 在重症患者中推动发病机理的内型和机制。在这个职业发展中 奖励，她的目标是获得FA代谢的重点培训；精通免疫细胞信号传导 炎症和激活抑制的途径；发展技能来设计，招募和保留一系列 重病的受试者探索患者特征和败血症诱导的IP的临床相关性 使用因果推理方法；并在复杂生物学数据的统计分析中建立专业知识。她会的 通过指导，课程，研究的传播和实践经验来实现这一目标 她未来的成功所必需的。

项目成果

Identifying a hyperinflammatory subphenotype of ARDS associated with worse outcomes: may ferritin help?

确定与较差结果相关的 ARDS 的高炎症亚表型：铁蛋白有帮助吗？

• DOI: 10.1136/thorax-2023-221131
• 发表时间: 2024
• 期刊: Thorax
• 影响因子: 10
• 作者: Torres,LisaK;Siempos,IliasI
• 通讯作者: Siempos,IliasI