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.

项目总结 脓毒症诱导的免疫麻痹(IP)与后续的和通常是长期的影响有关，包括 对继发性和机会性病原体的敏感性，以及可能导致最终结果的持续性免疫紊乱 在低度炎症和死亡中。免疫细胞代谢的改变和受损的细胞信号是 脓毒症所致IP的病理生理特点。有很强的科学前提支持这一有影响力的角色 脂肪酸(FA)及其酰基肉碱(AC)代谢产物在细胞能量代谢、免疫信号和 调节细胞因子的释放。这些概念突出了代谢物作为主动贡献者的潜在作用。 与疾病病理生理学有关，而不是仅仅代表潜在途径的后果。致信地址 丽莎·托雷斯，医学博士，硕士，提出这个职业发展奖的总体目标是 脓毒症IP的代谢和蛋白质生物标志物与最广泛接受的替代生物标志物的特征 IP、CD14+单核细胞表达HLADR。在一个多学科指导团队的协助下， 托雷斯在一组严重败血症和非败血症患者中提出了以下目标，根据存在情况进行分层 是否存在IP：(1)确定FA代谢异常与脓毒症所致IP的关系； (2)表征免疫麻痹反应蛋白(IPRPs)作为细胞介体和候选者的作用 与脓毒症诱导的IP相关的生物标志物；以及(3)探讨IP作为一种中介变量在 脓毒症和患者预后。在目标1中，托雷斯博士将测量脂肪酸氧化(FAO)的利用率并执行 用13C-FAs代谢示踪法评估入选患者(N=280)外周血单核细胞的AC合成。在《目标2》中，Dr。 Torres将使用THP-1单核细胞样细胞系和患者PBMC(目标1)来确定IPRP的影响 细胞激活的激动剂。她还将测量招募患者的血浆中的IPRP(目标1)。在《目标3》中， Torres博士将使用因果推理方法来估计IP作为中介对因果路径的影响 脓毒症和不良患者结局之间的关系。托雷斯博士的长期职业目标是成为一名独立的 脓毒症翻译调查和分子流行病学研究人员，从事理解 在危重病人中驱动发病机制的内型和机制。在这份职业发展中 获奖后，她的目标是获得FA代谢方面的重点培训；熟练掌握免疫细胞信号转导 炎症和激活抑制的途径；发展技能以设计、招募和保留一批 重症受试者探讨患者特征和脓毒症所致IP对预后的临床相关性 使用因果推理方法；并在复杂生物数据的统计分析方面积累专业知识。她会的 通过指导、课程作业、研究传播和实践经验来实现这一点 对她未来的成功来说是必不可少的。

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