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.

将临床前研究转化为治疗的数十年努力失败了。没有有效 分子靶向治疗败血症的疗法。流体的支持治疗方面取得了长足进展 复苏，及时的抗生素已经降低了急性期死亡率，但现在有很大的比例 败血症和败血性休克滥用发育，慢性重症疾病（CC​​I）。在CCI期间，长期 死亡率因继发感染和心血管原因而增加。预测最终命运 败血症患者，生存与死亡或CCI以及对继发感染反应的能力很困难。 败血症中的免疫反应通过超炎的动态重编程 病原体的免疫耐药性，使免疫反应取代炎症反应 公差，在几个小时/天内。白细胞粘附，最早的体内炎症反应，是 对“阻力”与“耐受性”的作用，并充当宿主免疫反应的“窗口”。 Sirtuins（Sirts），一种高度保守的家族或蛋白质，调节从超高向偏差的转移 炎症，包括啮齿动物败血症中的白细胞粘合剂。该项目将重点放在两个基本上 识别超炎性阶段的策略，并以特异性方式进行治疗。 项目1：建立基于临时的物理标记和生物标志物来区分 败血症阶段（差距1）：在此目标下，我们将建立：1）对白细胞的快速评估 （外周血单核细胞：PBMC）对次级刺激的粘附反应和2）SIRT1和2） SIRT2作为生物标志物，以鉴定败血症的低炎性阶段。我们将研究粘附反应 至少在三个患者的败血症/败血性休克进展过程中的SIRT生物标志物谱。 不同的时间点并将轮廓变化与临床结果相关联。 项目2：确定SIRT1的基于临时相位的调制的效果 2对次级刺激的响应（差距2）：使用不同的PBMC（单核细胞）在不同 败血症/败血性冲击进展和用SIRT1和SIRT 2处理的时间点2 通过遗传和药物方法激活/抑制，我将研究SIRT的影响 调节：1）单核细胞 - 内皮细胞粘附对次级刺激的反应，2）免疫 反应和3）败血症过程中的生物能源和代谢反应。 影响：这些研究的完成将1）识别标记/生物标志物以识别败血症阶段， 2）将PBMC的免疫代谢响应概况与败血症进展和患者相关 结果，3）识别SIRTS 1和2（以及可能其他代谢/炎症分子）为 相位特异性治疗剂。