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.

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