Critical Role of Nrf2 in Innate Immune Response and Survival During Sepsis

描述（由申请人提供）：我们的长期目标是了解调节全身炎症和脓毒症发病机制的宿主因素，仅在美国每年就有750，000人受到影响，并在全球范围内导致高死亡率。我们最近发现了一种新型宿主因子，即核因子-红细胞2 p45相关因子2（Nrf 2），它通过调节控制保护性细胞抗氧化剂诱导的补偿途径，在确定对败血症的易感性方面发挥着关键作用。nrf 2是一种碱性亮氨酸拉链转录因子，其调节抗氧化基因的表达，包括响应氧化和炎症应激的谷胱甘肽途径和血红素加氧酶。相对于野生型小鼠（Nrf 2 +/+），Nrf 2的整体破坏（Nrf 2-/-）显著降低了盲肠结扎穿孔（CLP）和内毒素处理后的存活率。我们假设Nrf 2调节宿主代偿机制，导致抗氧化基因的转录诱导，从而决定脓毒症期间的生存。Nrf 2依赖性代偿性抗氧化途径的破坏通过夸大先天免疫应答和诱发淋巴细胞增加凋亡来增加死亡率。这一提议将阐明Nrf 2依赖性调节脓毒症的免疫发病机制和CLP后的生存，并努力开发一种新的小分子激活剂靶向Nrf 2的干预策略。具体目标1：检验Nrf 2通过维持细胞氧化还原平衡防止先天免疫应答失调来决定CLP后存活的假设。具体目的2：检验Nrf 2通过减弱淋巴细胞凋亡改善CLP后存活率的假设。具体目的3：检验通过用小分子激活剂增加Nrf 2活性来干预脓毒症的假设。脓毒症的免疫发病机制仍然知之甚少。nrf 2在氧化应激调节、先天免疫应答和脓毒症期间的存活之间提供了一种新的联系。这些研究可能导致基于Nrf 2的新策略的开发，用于干预脓毒症和改善生存。

DESCRIPTION (provided by applicant): Our long-term objective is to understand the host factors that regulate the systemic inflammation and pathogenesis of sepsis, which affects 750,000 persons every year in United States alone and causes high mortality worldwide. We recently discovered a novel host factor, nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) that plays a critical role in determining susceptibility to sepsis by regulating a compensatory pathway that controls the induction of protective cellular antioxidants. Nrf2 is a basic leucine zipper transcription factor that regulates the expression of antioxidant genes including the glutathione pathway and heme oxygenase in response to oxidative and inflammatory stress. Global disruption of Nrf2 (Nrf2 -/-) dramatically decreased survival after cecal ligation and puncture (CLP) and endotoxin treatment relative to wild-type mice (Nrf2 +/+). We hypothesize that Nrf2 regulates a host compensatory mechanism that causes transcriptional induction of antioxidant genes, which determines survival during sepsis. Disruption of Nrf2-dependent compensatory antioxidant pathways increases mortality by exaggerating the innate immune response and predisposing lymphocytes to increase apoptosis. This proposal will shed light on the Nrf2-dependent regulation of immunopathogenesis of sepsis and survival after CLP and strives to develop an intervention strategy targeting Nrf2 with a novel small-molecule activator. Specific Aim 1: To test the hypothesis that Nrf2 determines survival after CLP by protecting against deregulation of innate immune response by maintaining cellular redox balance. Specific Aim 2: To test the hypothesis that Nrf2 improves survival after CLP by attenuating apoptosis of lymphocytes. Specific Aim 3: To test the hypothesis of intervening sepsis by increasing Nrf2 activity with a small-molecule activator. The immunopathogenesis of sepsis remains poorly understood. Nrf2 provides a novel link between the regulation of oxidative stress, the innate immune response.and survival during sepsis. These studies may lead to the development of novel strategies based on Nrf2 for intervening in sepsis and improving survival.