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.

总结： 脓毒症是发病率和死亡率的重要原因。严重脓毒症合并多器官损伤， 急性肺损伤（ALI）引起的呼吸衰竭经常作为死亡的直接原因。在败血症期间， 白细胞和结构细胞的无限制刺激可诱导全身炎症反应 综合征（SIRS）导致组织损伤和对医院感染的易感性。不幸的是，由于没有 有效的药物可用于治疗这些个体中发展中的SIRS/器官损伤， 需要进一步分析导致SIRS发生和发展的复杂事件。远景目标 该项目的目的是确定吞噬细胞功能的内源性抑制剂， 炎症反应，同时恢复抗微生物效应功能。这种更新是建立在出版和 在研究磷酸酶和张力蛋白同源物PTEN的作用时产生的初步数据， microRNA介导的MyD 88降解和脓毒症期间SIRS的产生。我们发现， 缺乏增加脓毒症小鼠的死亡率; miR 21（靶向PTEN的microRNA）是一种体内平衡因子， 巨噬细胞炎症反应的调节因子，防止过度糖酵解降低SIRS 发展，ALI形成和改善动物生存。我们的初步数据表明，除了 控制转录程序，PTEN还直接抑制炎性体（细胞内炎性细胞因子）。 平台）依赖于强效炎症介质的释放。PTEN还刺激脂肪酸氧化（FAO）， 抑制炎症此外，我们还发现，miR 21抑制了参与以下过程的基因的表达： FAO，这与动物存活率下降，肺部炎症和死亡率增加有关。从这些 研究发现，我们提出了我们的中心假设，即在脓毒症期间，骨髓特异性信号沿着 miR 21/PTEN/FAO轴在脓毒症期间变得失调并驱动肺损伤和致死性。这一假设 将通过测试1）PTEN在脓毒症中吞噬细胞中炎性小体活化中的作用和2） 确定miR 21/PTEN轴在脓毒症期间肺损伤和死亡率中的作用。我们将采用一系列 最先进的技术，沿着上位性和功能获得方法，以揭示新的信号程序 最终可能影响全身感染期间的ALI和死亡率。PI的组合 在败血症，肺免疫学和炎症方面的经验，合作者组成的团队，以及 范德比尔特大学医学中心的环境确保了这项工作的完成。的 确定维持脓毒症的特定组分及其作用模式可以确定 治疗干预导致宿主脆弱性环境中的免疫反应性改善，并且可能 提出了在过度炎症的情况下抑制免疫反应的策略。