Targeting brain inflammation and neurocognitive dysfunction in sepsis

项目摘要 脓毒症是一种严重的临床疾病，由宿主失调引起的危及生命的器官功能障碍 对感染的反应。高达70%的脓毒症患者和超过50%的脓毒症幸存者发展为 神经认知功能障碍，一种称为脓毒症相关脑病（SAE）的衰弱性疾病。而 临床和实验数据都表明炎症在SAE发病机制中的作用，确切的说， 导致脑炎症和神经认知功能障碍的原因和分子机制是 没有很好地理解。我们最近已经表明，宿主细胞RNA，包括microRNA，被释放到 脓毒症期间血液循环和循环宿主RNA水平与脓毒症密切相关 动物的严重性。此外，不同物种（人类和啮齿动物）和器官的细胞外（ex）RNA （脾和心脏）和某些富含尿苷的miRNAs可以作为损伤相关的分子模式， DAMPs通过TLR 7依赖性机制在外周免疫中驱动促炎反应。 细胞、小胶质细胞和完整动物。根据这些信息和其他已发表的文献，我们 假设由ex-miRNA-TLR 7信号传导驱动先天免疫激活作为关键机制发挥作用 脑炎症和脓毒症后神经认知功能障碍。为了验证这一假设，我们建议 目的1：证明循环ex-miRNAs在脑炎症中的作用， 脓毒症;目的2：评估血浆外泌体作为ex-miRNA载体在脑炎症中的作用;目的3： 为了测试ex-miRNAs® TLR 7信号传导对脓毒症中脑炎症的贡献;目的4：为了证明 靶向ex-miRNA® TLR 7信号通路可改善脓毒症患者的长期神经认知功能 幸存者本提案的总体目标是研究ex-miRNA® TLR 7的功能和机制。 脓毒症后脑炎症和神经认知功能障碍的信号传导。预期结果将 为脓毒症相关脑病的发病机制提供了机制性见解， 治疗目标

PROJECT SUMMARY Sepsis is a serious clinical condition with life-threatening organ dysfunction caused by a dysregulated host response to infection. Up to 70% of septic patients and more than 50% sepsis survivors develop neurocognitive dysfunction, a debilitating condition termed sepsis-associated encephalopathy (SAE). While both clinical and experimental data suggest the role of inflammation in the pathogenesis of SAE, the exact causes and the molecular mechanisms leading to cerebral inflammation and neurocognitive dysfunction are not well understood. We have recently shown that host cellular RNAs including microRNAs are released into the blood circulation during sepsis and that circulating host RNA levels are closely associated with sepsis severity in animals. Moreover, extracellular (ex) RNA of different species (human and rodents) and organs (spleen and heart) and certain uridine-rich miRNAs can function as damage-associated molecular patterns (DAMPs) and drive proinflammatory responses through a TLR7-dependent mechanism in peripheral immune cells, in microglial cells, and in intact animals. Based on these information and other published literatures, we hypothesize that innate immune activation driven by ex-miRNA-TLR7 signaling functions as a key mechanism in cerebral inflammation and neurocognitive dysfunction following sepsis. To test the hypothesis, we propose the following specific aims: Aim 1: To demonstrate the role of circulating ex-miRNAs in brain inflammation in sepsis; Aim 2: To evaluate the role of plasma exosomes, as ex-miRNA carriers, in brain inflammation; Aim 3: To test the contribution of ex-miRNAs®TLR7 signaling to brain inflammation in sepsis; Aim 4: To demonstrate that targeting ex-miRNA®TLR7 signaling pathways improves the long-term neurocognitive function in sepsis survivors. The overall goal of this proposal is to investigate the function and mechanisms of ex-miRNA®TLR7 signaling in brain inflammation and neurocognitive dysfunction following sepsis. The anticipated results will provide mechanistic insights into the pathogenesis of sepsis-associated encephalopathy and potential novel therapeutic targets.