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 脓毒症诱导的免疫麻痹（IP）与后果相关，通常是长期影响，包括 对继发性和机会性病原体的易感性，以及持续的免疫紊乱， 轻度炎症和死亡免疫细胞代谢的改变和受损的细胞信号传导是 脓毒症诱导IP的病理生理学特征。有一个强有力的科学前提支持的影响作用 脂肪酸（FA）及其酰基肉毒碱（AC）代谢产物在细胞能量代谢、免疫信号传导和 调节细胞因子释放。这些概念突出了代谢物作为活性贡献者的潜在作用 疾病的病理生理学，而不是仅仅代表潜在途径的后果。解决 丽莎托雷斯，医学博士，硕士，提出了这个职业发展奖的总体目标， 相对于最广泛接受的替代生物标志物，表征脓毒性IP的代谢和蛋白质生物标志物 IP、CD 14+单核细胞HLA-DR表达。在多学科指导团队的协助下， 托雷斯提出了以下目标，在一个严重脓毒症和非脓毒症患者的队列中，按存在分层 （1）确定FA代谢失调与脓毒症诱导的IP之间的关系; (2)表征免疫瘫痪反应蛋白（IPRPs）作为细胞介质和候选物的作用 与脓毒症诱导的IP相关的生物标志物;和（3）探索IP作为脓毒症诱导的IP之间的中介变量的作用。 脓毒症和患者结局。在目标1中，托雷斯博士将测量脂肪酸氧化（FAO）利用率，并执行 用13 C-FA进行代谢示踪以评估来自招募的患者（N=280）的PBMC中的AC合成。在目标2中，博士 托雷斯将使用THP-1单核细胞样细胞系和患者PBMC（目的1）来确定IPRP的影响 激动剂对细胞活化的影响。她还将测量招募患者血浆中的IPRP（目标1）。在目标3中， 博士托雷斯将使用因果推理方法来估计IP作为因果途径的中介物的效果 脓毒症和病人不良反应之间的联系托雷斯博士的长期职业目标是成为一名独立的 脓毒症转化调查和分子流行病学研究员，从事了解 内型和机制，驱动发病机制之间的危重病人。在这个职业发展中 她的目标是获得FA代谢方面的重点培训;精通免疫细胞信号传导 炎症途径和抑制激活;发展技能，以设计，招募和保留一个队列， 危重受试者，以探索患者特征和脓毒症诱导的IP对结局的临床相关性 使用因果推理方法;建立复杂生物数据统计分析的专业知识。她将 通过指导，课程，研究传播和实践经验，所有 这是她未来成功的必要条件。

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