Immune Function in Sepsis: Role of Sirtuin

几十年来将临床前研究转化为治疗方法的努力都失败了；没有有效的方法 治疗脓毒症的分子靶向疗法。体液支持治疗的实质性进展 复苏，及时的抗生素降低了急性期的死亡率，但现在有相当大的比例 大多数败血症和感染性休克患者发展为慢性危重病(CCI)。在CCI期间，长期 继发感染和心血管原因导致的死亡率增加。预测人类的最终命运 脓毒症患者，生存与死亡或CCI和应对继发感染的能力是困难的。 脓毒症的免疫反应经历了一个动态的重新编程，从高炎症到 病原体的免疫抵抗力，让位于免疫的低炎性反应 容忍度，在小时/天内。白细胞黏附是体内最早的炎症反应，是 在“抵抗力”与“耐受性”之间起着重要的作用，是宿主免疫反应的“窗口”。 Sirtuins(sirtuins，SIRT)是一个高度保守的家族或蛋白质，调节着从高水平到低水平的转变。 炎症，包括啮齿动物脓毒症中的白细胞黏附。这个项目将专注于两个基本的 确定高炎症阶段与低炎症阶段的策略，并以特定阶段的方式进行治疗。 项目1：建立基于时间的生理标记和生物标记以区分 脓毒症阶段(GAP 1)：在这一目标下，我们将建立：1)体外快速测定白细胞 (外周血单个核细胞：PBMC)对二次刺激的黏附反应和2)SIRT1和 以SIRT2为生物标志物，识别脓毒症的低炎性阶段。我们将研究黏附反应 每名患者在脓毒症/感染性休克进展过程中至少有3个SIRT生物标志物 不同的时间点，并将轮廓变化与临床结果相关联。 项目2：确定基于时间的SIRT1特定相位调制的影响 和2关于对二次刺激的反应(Gap 2)：在不同的条件下使用患者的PBMC(单核细胞) 脓毒症/感染性休克进展的时间点及SIRT1和SIRT2的治疗 激活/抑制用遗传学和药理学方法，我将研究SIRT的作用 调节：1)单核细胞-内皮细胞对二次刺激的黏附反应，2)免疫 3)脓毒症进展过程中的生物能量和代谢反应。 影响：这些研究的完成将1)确定识别脓毒症阶段的标志物/生物标志物， 2)脓毒症进展过程中PBMC的免疫代谢反应与患者的相关性 结果，3)确定SIRT 1和2(以及潜在的其他代谢/炎症分子)为 特定阶段的治疗剂。

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.