Necroinflammatory Cell Death in Sepsis

脓毒症中的坏死性炎症细胞死亡

• 批准号: 10470307
• 负责人: Edward James Schenck
• 金额: $ 19.49万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10470307
• 关键词: Accident and Emergency department; Acute; Address; Admission activity; Affect; Apoptosis; Area; Benign; Biological Markers; Blood; Blood Circulation; Cell Death; Cell Death Process; Cell physiology; Cells; Clinical; Clinical Trials; Complex; Data; Development; Diagnosis; Emergency Department patient; Enrollment; Epithelial; Functional disorder; Goals; HMGB1 gene; Heterogeneity; Hospitals; Human; Immune; Immune response; Immune system; Immunologics; Immunotherapy; Infection; Inflammation; Inflammatory; Innate Immune Response; Innate Immune System; Intensive Care Units; Lead; Ligands; Measures; Methodology; Mitochondrial DNA; Modeling; Molecular; Molecular Target; Morbidity - disease rate; Organ; Organ failure; Outcome; Pathogenesis; Pathway interactions; Patients; Pattern; Phenotype; Physiological; Plasma; Production; Protein-Serine-Threonine Kinases; Proteomics; RIPK1 gene; RIPK3 gene; Research; Resuscitation; Risk; Role; Sepsis; Septic Shock; Severities; Syndrome; TNF gene; TNF-related apoptosis-inducing ligand; Testing; Time; Treatment Factor; Work; antimicrobial; biobank; biomarker development; biomarker panel; cohort; follow-up; immunoregulation; improved; insight; member; mortality; mortality risk; novel; pathogen; predictive marker; receptor; recruit; sample collection; septic; septic patients; tool; treatment effect; ward

PROJECT SUMMARY/ABSTRACT: Sepsis is a deadly infection characterized by a dysregulated host immune response. Outcomes have failed to improve despite decades of research. The immune response in sepsis is varied. Immunologic therapy has failed in part due to the heterogeneity of the syndrome. Beyond the immunologically silent apoptosis, necroinflammatory cell death, commonly necroptosis, is immunologically stimulating and can perpetuate inflammation in sepsis. The initiation and coordination of necroinflammatory cell death is complex. TNF related apoptosis inducing ligand (TRAIL) coordinates cellular processes associated with increased apoptosis and necroinflammatory cell death. Receptor interacting serine/threonine kinase 3 (RIPK3) is essential to necroptotic cell death. Our work has shown that RIPK3 is increased in septic patients in the intensive care unit in parallel with increased organ dysfunction and is associated with poor outcomes. In the ICU, we have demonstrated that lower TRAIL is associated with higher RIPK3 and increased organ dysfunction. In this project, we will examine TRAIL and RIPK3 at three time points, in the emergency department and ICU. We hypothesize that necroinflammatory cell death, characterized by high RIPK3 and low TRAIL will identify those who progress to sepsis and septic shock and that there will be novel patterns of necroinflammatory cell death in patients at increased risk of death with sepsis. AIM 1 will create a human cohort of patients at three critical time points during an acute admission to the hospital. The first is soon after admission to the emergency department prior to resuscitation and the administration of antimicrobial therapy. The follow up blood draws are obtained following admission to the ward or ICU when organ dysfunction is established and therapy has been initiated. AIM 2 will examine the relationship between TRAIL and RIPK3 and sepsis, septic shock and mortality through two methodologies. The first will examine whether TRAIL and RIPK3 will increase our ability to diagnose sepsis when combined with physiologic sepsis prediction tools in the emergency department. The second will evaluate the effect of the follow up TRAIL and RIPK3 on outcomes, after modeling the effect of time dependent patient, pathogen and treatment factors. For AIM 3, we will measure levels of a targeted mechanistic cell death panel including, RIPK1, RIPK3, MLKL, along with key damage associated molecular patterns, mtDNA and HMGB1. We will also evaluate a broader necroinflammatory biomarker panel in a proteomics platform. We will then evaluate whether there are clusters of patients defined by relative biomarker levels together with physiologic variables. We will examine if these patient clusters have differential outcomes. If the aims of this proposal are achieved, we will have useful information concerning the role of necroinflammatory cell death in human sepsis from multiple time points. Results from this study may offer insight into the development of biomarkers for predictive enrichment of clinical trials targeting necroinflammatory cell death.

项目总结/文摘: