Necroinflammatory Cell Death in Sepsis

脓毒症中的坏死性炎症细胞死亡

• 批准号: 10301742
• 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/10301742
• 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.

项目概要/摘要： 败血症是一种致命的感染，其特征是宿主免疫反应失调。 Outcomes have failed to 尽管进行了数十年的研究，但仍有所改善。脓毒症的免疫反应是多种多样的。免疫疗法失败 部分原因是该综合征的异质性。除了免疫沉默的细胞凋亡之外， 坏死性炎症细胞死亡，通常是坏死性凋亡，具有免疫刺激作用并且可以永久存在 inflammation in sepsis.坏死性炎症细胞死亡的启动和协调是复杂的。 TNF related 细胞凋亡诱导配体 (TRAIL) 协调与细胞凋亡增加相关的细胞过程， 坏死性炎症细胞死亡。受体相互作用丝氨酸/苏氨酸激酶 3 (RIPK3) 对于坏死性凋亡至关重要 细胞死亡。我们的工作表明，重症监护室脓毒症患者的 RIPK3 水平同时升高 器官功能障碍增加，并与不良结果相关。在 ICU，我们已经证明 较低的 TRAIL 与较高的 RIPK3 和增加的器官功能障碍相关。在这个项目中，我们将检查 急诊科和 ICU 三个时间点的 TRAIL 和 RIPK3。我们假设 以高 RIPK3 和低 TRAIL 为特征的坏死性炎症细胞死亡将识别那些进展为 败血症和败血性休克，并且患者中将出现坏死性炎症细胞死亡的新模式 脓毒症死亡风险增加。 AIM 1 将在三个关键时间点创建一个人类患者队列 急性入院期间。第一个是在进入急诊室后不久 复苏和抗菌治疗的管理。后续抽血如下 当确定器官功能障碍并开始治疗时，入住病房或 ICU。 AIM 2 将 通过两种方法检查 TRAIL 和 RIPK3 与脓毒症、感染性休克和死亡率之间的关系 方法论。第一个将检查 TRAIL 和 RIPK3 是否会提高我们诊断脓毒症的能力 与急诊科的生理性脓毒症预测工具相结合。第二个将评估 在对时间依赖性患者的影响进行建模后，跟踪 TRAIL 和 RIPK3 对结果的影响， 病原体和治疗因素。对于 AIM 3，我们将测量目标机械性细胞死亡组的水平 包括 RIPK1、RIPK3、MLKL，以及关键损伤相关分子模式、mtDNA 和 HMGB1。 我们还将在蛋白质组学平台中评估更广泛的坏死性炎症生物标志物组。我们随后将 评估是否存在由相对生物标志物水平和生理学定义的患者群 变量。我们将检查这些患者群是否有不同的结果。如果该提案的目标是 如果实现了，我们将获得有关坏死性炎症细胞死亡在人类脓毒症中的作用的有用信息 从多个时间点来看。这项研究的结果可能有助于了解生物标志物的开发 针对坏死性炎症细胞死亡的临床试验的预测丰富。