Phosphatase and tensin homolog PTEN actions in polymicrobial sepsis

磷酸酶和张力蛋白同源物 PTEN 在多种微生物败血症中的作用

• 批准号: 10005956
• 负责人: C. Henrique Serezani
• 金额: $ 57.07万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10005956
• 关键词: Academic Medical Centers; Acute Lung Injury; Animals; Anti-Inflammatory Agents; Apoptosis; Binding; Blood; Blood Vessels; Butyrates; Cells; Cellular Structures; Cessation of life; Complex; Data; Development; Disease; Ensure; Environment; Enzymes; Equilibrium; Event; Exhalation; Exhibits; Fatty Acids; Gene Expression; Generations; Genetic; Genetic Transcription; Glycolysis; Goals; Homeostasis; Host Defense; Human; Hydroxyl Radical; IL18 gene; IL1R1 gene; Immune; Immune response; Immunology; Individual; Infiltration; Inflammasome; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Intensive Care Units; Interleukin-1 beta; Lead; Leukocytes; Lipids; Lung; Lung Inflammation; Maintenance; Mediating; Medicine; Metabolic; Metabolic Pathway; MicroRNAs; Molecular; Molecular Target; Morbidity - disease rate; Mus; Myelogenous; Myeloid Cells; Nonesterified Fatty Acids; Nosocomial Infections; Nucleotides; Operative Surgical Procedures; Organ; Organ failure; Outcome; PTEN gene; Pathway interactions; Phagocytes; Phosphorylation; Plant Roots; Predisposition; Production; Protein phosphatase; Publishing; RNA Stability; Respiratory Failure; Role; Sepsis; Series; Serum; Severity of illness; Shapes; Signal Transduction; Site; Syndrome; Systemic Inflammatory Response Syndrome; Systemic infection; Techniques; Testing; Therapeutic; Therapeutic Intervention; Tissues; Trauma; Untranslated RNA; Work; antimicrobial; arm; cytokine; experience; experimental study; fatty acid metabolism; fatty acid oxidation; gain of function; improved; inhibitor/antagonist; insight; lung injury; macrophage; metabolic profile; mortality; neutrophil; novel; novel therapeutics; organ injury; pleiotropism; polymicrobial sepsis; pre-clinical; prevent; programs; receptor; septic; targeted treatment; tissue injury

SUMMARY: Sepsis is a significant cause of morbidity and mortality. Severe sepsis complicated with multiple organ injury and acute lung injury (ALI)-induced respiratory failure frequently serves as a direct reason of death. During sepsis, unrestrained stimulation of leukocytes and structural cells can induce Systemic Inflammatory Response Syndrome (SIRS) resulting in tissue injury and susceptibility to nosocomial infection. Unfortunately, as no effective medicine is available to treat the developing SIRS/organ injury in these individuals, there is a strong need to further dissect the complex events that lead to the initiation and progression of SIRS. The long-term goal of this project is to identify endogenous inhibitors of phagocyte function that could decrease different arms of the inflammatory response while restoring antimicrobial effector functions. This renewal is built upon published and preliminary data generated while investigating the role of the phosphatase and tensin homolog PTEN in microRNA-mediated MyD88 degradation and the generation of SIRS during sepsis. We found that PTEN deficiency enhances mortality in septic mice; that miR21 (a microRNA that targets PTEN) is a homeostatic regulator of macrophage inflammatory response and that preventing excessive glycolysis decreases SIRS development, ALI formation and improves animal survival. Our preliminary data suggest that in addition to controlling transcriptional programs, PTEN also directly inhibits the inflammasome (intracellular inflammatory platforms)-dependent release of potent inflammatory mediators. PTEN also stimulates fatty acid oxidation (FAO), which inhibits inflammation. Furthermore, we also found that miR21 inhibits the expression of genes involved in FAO, which correlates with decreased animal survival, increased lung inflammation and mortality. From these findings, we formulated our central hypothesis that during sepsis, myeloid-specific signaling along the miR21/PTEN/FAO axis becomes dysregulated and drives lung injury and lethality during sepsis. This hypothesis will be examined by testing the 1) role of PTEN in inflammasome activation in phagocytes in sepsis and 2) Determine the role of the miR21/PTEN axis in lung injury and mortality during sepsis. We will employ a series of state-of-the-art techniques, along with epistatic and gain of function approaches to unveil new signaling programs that ultimately might influence ALI and mortality during systemic infections. The combination of the PI’s experience in sepsis, lung immunology and inflammation, the assembled team of collaborators, and the environment at Vanderbilt University Medical Center ensure that this work will be accomplished. The identification of specific components and their modes of action in maintenance of sepsis may identify targets for therapeutic intervention resulting in improved immune responsiveness in settings of host vulnerability, and may suggest strategies to dampen the immune response in settings of exaggerated inflammation.

摘要： 脓毒症是发病率和死亡率的重要原因。严重脓毒症合并多脏器损伤 急性肺损伤(ALI)所致的呼吸衰竭常常是死亡的直接原因。在败血症期间， 无节制地刺激白细胞和结构细胞可引起全身炎症反应 导致组织损伤和医院感染易感性的综合征(SIRS)。不幸的是，因为不是 有有效的药物可以治疗这些人发展中的SIRS/器官损伤，有很强的 需要进一步剖析导致SIRS启动和发展的复杂事件。长期目标 这个项目的目的是找出吞噬细胞功能的内源性抑制物，这些抑制物可以减少不同的手臂 炎症反应，同时恢复抗菌效应器功能。此次续订建立在已发布和 初步数据是在研究磷酸酶和张力蛋白同源基因PTEN在 脓毒症时MicroRNA介导的MyD88降解和SIRS的产生我们发现PTEN 缺乏会增加败血症小鼠的死亡率；miR21(一种靶向PTEN的微RNA)是一种动态平衡 巨噬细胞炎症反应调节因子和防止过度糖酵解降低SIRS 发展，形成ALI，提高动物存活率。我们的初步数据表明，除了 控制转录程序，PTEN也直接抑制炎症体(细胞内炎症 平台)依赖于强效炎症介质的释放。PTEN还刺激脂肪酸氧化(FAO)， 它能抑制炎症。此外，我们还发现miR21抑制参与基因的表达。 与动物存活率下降相关的粮农组织增加了肺部炎症和死亡率。从这些 结果，我们提出了我们的中心假设，即在脓毒症期间，髓系特异性信号沿 在脓毒症过程中，miR21/PTEN/FAO轴失调，导致肺损伤和致死性改变。这一假设 将通过测试1)PTEN在脓毒症吞噬细胞中炎性小体激活中的作用和2)来检验 确定miR21/PTEN轴在脓毒症时肺损伤和死亡率中的作用。我们将聘用一系列 最先进的技术，以及上位法和功能获得法，以揭示新的信号程序 这最终可能会影响ALI和系统性感染期间的死亡率。PI的组合 在脓毒症、肺部免疫学和炎症方面的经验，组建的合作者团队，以及 范德比尔特大学医学中心的环境保证了这项工作的完成。这个 确定脓毒症维持过程中的特定成分及其作用模式可以确定目标 治疗干预导致在宿主易受攻击的环境中改善免疫反应性，并且可以 建议在炎症过度的情况下抑制免疫反应的策略。