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.

概括： 败血症是发病率和死亡率的重要原因。严重的败血症因多个器官损伤而复杂 急性肺损伤（ALI）诱导的呼吸衰竭通常是死亡的直接原因。在败血症期间， 白细胞和结构细胞的不受约束的模拟会诱导全身炎症反应 综合征（SIRS）导致组织损伤和对医院感染的敏感性。不幸的是，没有 有效的医学可用于治疗这些人的发育中的SIRS/器官损伤，有一个强大的 需要进一步剖析导致SIRS主动性和进展的复杂事件。长期目标 该项目的是识别吞噬作用的内源性抑制剂，该抑制剂可能会降低不同的臂 在恢复抗菌效应子功能的同时，炎症反应。此续约是建立在出版和 在研究磷酸酶和tensin同源物在中的作用时产生的初步数据 MicroRNA介导的MyD88降解和败血症期间的SIRS产生。我们发现Pten 化粪池小鼠的缺乏增强死亡率； MiR21（靶向PTEN的microRNA）是一种体内平衡 巨噬细胞炎症反应的调节剂和防止糖酵解过量的调节器会降低SIRS 发展，阿里形成并改善动物的生存。我们的初步数据表明，除了 控制转录程序，PTEN还直接抑制炎症体（细胞内炎症 平台）依赖于潜在炎症介质的释放。 PTEN还刺激脂肪酸氧化（FAO）， 抑制会影响炎症。此外，我们还发现miR21抑制了涉及的基因的表达 粮农组织与动物存活的降低相关，肺部感染和死亡率增加。从这些 调查结果，我们提出了我们的中心假设，即在败血症中，髓样特异性信号沿着 MiR21/PTEN/FAO轴的失调失调，败血症期间驱动肺损伤和致死性。这个假设 通过测试1）PTEN在败血症和2的吞噬细胞中的炎症体激活中的作用来检查。 确定miR21/PTEN轴在败血症过程中的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，以及揭露新信号程序的上位和功能方法的增益 最终可能会影响全身感染期间的ALI和死亡率。 PI的组合 败血症，肺免疫学和炎症，合作者团队的经验， 范德比尔特大学医学中心的环境确保将完成这项工作。这 识别特定组件及其在维持败血症方面的作用方式可能会确定目标的目标 治疗干预措施，导致宿主脆弱性的免疫反应提高，并且可能 建议在夸张的注射环境中抑制免疫响应的策略。