Immune Function in Sepsis: Role of Sirtuin

脓毒症中的免疫功能：Sirtuin 的作用

• 批准号: 10623046
• 负责人: Vidula Vachharajani
• 金额: $ 40.25万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10623046
• 关键词: Acute; Adhesions; Antibiotics; Biological Markers; Cardiovascular system; Cause of Death; Cell Adhesion; Cessation of life; Chronic; Clinical; Critical Illness; Endothelial Cells; Family; Genetic; Hour; Immune Tolerance; Immune response; Inflammation; Inflammatory; Inflammatory Response; Intensive Care Units; Leukocytes; Liquid substance; Metabolic; Outcome; Patient-Focused Outcomes; Patients; Peripheral Blood Mononuclear Cell; Phase; Physiological; Proteins; Resistance; Resuscitation; Rodent; Role; SIRT1 gene; Secondary to; Sepsis; Septic Shock; Sirtuins; Stimulus; Therapeutic Agents; Time; Translating; biomarker identification; immune function; immune resistance; in vitro Assay; in vivo; molecular targeted therapies; monocyte; mortality; pathogen; pharmacologic; pre-clinical research; response; secondary infection; septic patients

Decades long effort to translate pre-clinical research into treatments have failed; there are no effective molecular-targeted therapies to treat sepsis. Substantial progress in supportive treatments with fluid resuscitation, timely antibiotics have decreased acute-phase mortality but now a significant proportion of sepsis and septic shock victims develop, chronic critical illness (CCI). During CCI, the long term mortality increases from secondary infections and cardiovascular causes. Predicting ultimate fate of sepsis patients, survival versus death or CCI and ability to respond to secondary infections is difficult. Immune response in sepsis undergoes a dynamic reprogramming from hyper-inflammation with immune resistance of pathogen that gives way to a hypo-inflammatory response with immune tolerance, within hours/days. Leukocyte adhesion, earliest in vivo inflammatory response, is instrumental to the “resistance” vs. “tolerance” and serves as a “window” to the host immune response. Sirtuins (SIRTs), a highly conserved family or proteins regulate the shift from hyper- to hypo- inflammation, including leukocyte adhesion in rodent sepsis. This project will focus on two basic strategies in to identify the hyper- vs. hypo-inflammatory phase and treat in a phase-specific manner. Project 1: Establish temporal based physiological marker and biomarkers to distinguish sepsis phases (GAP 1): Under this aim, we will establish: 1) A rapid in vitro assay of leukocyte (peripheral blood mononuclear cells: PBMC) adhesion response to secondary stimuli and 2) SIRT1 and SIRT2 as biomarkers, to identify hypo-inflammatory phase of sepsis. We will study adhesion response and SIRT biomarker profile during sepsis/septic shock progression in each patients at least at three different time points and correlate the profile changes with clinical outcomes. Project 2: Determine the effect of temporal based phase-specific modulations of SIRT1 and 2 on response to secondary stimuli (Gap 2): Using patient PBMCs (monocytes) at different time points during sepsis/septic shock progression and treating with SIRT1 and SIRT 2 activation/inhibition with genetic and pharmacological approaches, I will study the effect of SIRT modulation on: 1) Monocyte-endothelial cell adhesion response to secondary stimuli, 2) Immune response and 3) Bioenergy and metabolic responses during sepsis progression. Impact: The completion of these studies will 1) Identify markers/biomarkers to identify sepsis phases, 2) Correlate the immuno-metabolic response profile of PBMCs during sepsis progression and patient outcomes, 3) Identify SIRTs 1 and 2 (and potentially other metabolic/inflammatory molecules) as phase-specific therapeutic agents.

几十年来将临床前研究转化为治疗方法的努力失败了，没有有效的方法； 治疗脓毒症的分子靶向疗法在液体支持治疗方面取得了实质性进展。 复苏、及时使用抗生素降低了急性期死亡率，但现在比例很高 败血症和败血性休克患者罹患慢性危重病 (CCI)，这是一种长期的疾病。 继发感染和心血管原因导致的死亡率增加。预测最终命运。 脓毒症患者的生存与死亡或 CCI 以及对继发感染的反应能力是困难的。 脓毒症中的免疫反应经历了过度炎症的动态重编程 病原体的免疫抵抗，让位于免疫的低炎症反应 数小时/天内的耐受性是最早的体内炎症反应。 有助于“抵抗”与“耐受”，并充当宿主免疫反应的“窗口”。 Sirtuins (SIRT) 是一个高度保守的家族或蛋白质，调节从高到低的转变。 炎症，包括啮齿动物败血症中的白细胞粘附，该项目将重点关注两个基本问题。 识别高炎症阶段与低炎症阶段并以特定阶段的方式进行治疗的策略。 项目1：建立基于时间的生理标记和生物标记来区分 败血症阶段 (GAP 1)：在此目标下，我们将建立：1) 白细胞的快速体外测定 （外周血单核细胞：PBMC）对二次刺激的粘附反应和2）SIRT1和 SIRT2 作为生物标志物，用于识别脓毒症的低炎症阶段我们将研究粘附反应。 每位患者在败血症/败血性休克进展期间至少进行 3 次 SIRT 生物标志物分析 不同时间点并将概况变化与临床结果相关联。 项目 2：确定 SIRT1 基于时间的特定相位调制的效果 和 2 对二次刺激的反应（间隙 2）：在不同的时间使用患者 PBMC（单核细胞） 脓毒症/脓毒性休克进展期间的时间点以及 SIRT1 和 SIRT 2 治疗 通过遗传和药理学方法激活/抑制，我将研究 SIRT 的效果 调节：1) 单核细胞-内皮细胞对次级刺激的粘附反应，2) 免疫 反应和 3) 脓毒症进展期间的生物能和代谢反应。 影响：这些研究的完成将 1) 识别标志物/生物标志物以识别脓毒症阶段， 2) 将脓毒症进展期间 PBMC 的免疫代谢反应谱与患者相关联 结果，3) 将 SIRT 1 和 2（以及可能的其他代谢/炎症分子）确定为 阶段特异性治疗剂。