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: 8762864
• 负责人: C. Henrique Serezani
• 金额: $ 39万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 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 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8762864
• 关键词: Accounting; Acute; Adaptor Signaling Protein; Agonist; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Bacterial Infections; Binding; Cessation of life; Characteristics; Chronic; Data; Development; Disease; Endotoxins; Event; Exhibits; Failure; Gene Silencing; Goals; Host Defense; Human; Immune; Immune response; Immune system; Immunity; Immunosuppression; In Vitro; Infection; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Intensive Care Units; Interleukin-1; Longitudinal Studies; Lung; Macrophage Activation; Maintenance; Mediating; Mediator of activation protein; MicroRNAs; Modeling; Modification; Molecular; Morbidity - disease rate; Mus; Myelogenous; NF-kappa B; Natural Immunity; Nosocomial Infections; Operative Surgical Procedures; Organ; Outcome; PTEN gene; Pathogenesis; Pathway interactions; Patients; Phagocytes; Phase; Phosphoric Monoester Hydrolases; Phosphorylation; Post-Transcriptional Regulation; Predisposition; Production; Receptor Activation; Regulatory Pathway; Role; Secondary to; Sepsis; Sepsis Syndrome; Signal Pathway; Signal Transduction; Small Interfering RNA; Staging; TLR3 gene; TLR4 gene; Testing; Therapeutic Intervention; Toll-like receptors; Trauma; Tumor Suppressor Proteins; United States; Work; antimicrobial; base; improved; in vivo; inhibitor/antagonist; insight; mRNA Transcript Degradation; macrophage; microbial; mortality; novel; p65; pathogen; programs; protective effect; public health relevance; receptor; response; secondary infection; septic; therapeutic target; transcription factor

DESCRIPTION (provided by applicant): Sepsis accounts for 250,000 deaths annually in the United States alone. Unrestrained stimulation of phagocytes can induce Systemic Inflammatory Response Syndrome (SIRS) resulting in failure of multiple systemic organs. Prolonged SIRS leads to enhanced susceptibility to nosocomial infection. Phagocyte recognition of microbial products is mediated by Toll like receptors via activation of Toll/IL-1R (TIR) adaptor MyD88-dependent NF-kB activation. There are numerous endogenous brakes involved in TLR activation, including phosphatases SHIP-1 and DUSP. The role of the phosphatase and tensin homolog PTEN in controlling macrophage activation and its role in controlling polymicrobial sepsis is unknown. This project is based on preliminary data showing that PTEN inhibits MyD88 expression by controlling actions of specific microRNAs. Furthermore, while PTEN activation has protective effects in acute sepsis, enhanced and chronic PTEN expression produces deleterious effects favoring endotoxin tolerance and possibly secondary infection. The hypothesis to be tested is that although PTEN protects against overwhelming inflammatory responses early in acute sepsis, excessive PTEN expression is responsible for both the initiation and maintenance of sepsis-induced immunoparalysis states by impairing TLR activation in phagocytes. These studies will increase our overall understanding of how innate immunity works, and will produce insights regarding the pathogenesis of acute sepsis and enhanced susceptibility to secondary infection in deleterious conditions. We propose the following specific aims: 1 - Determine how PTEN controls transcriptional and post-transcriptional modifications involved in MyD88 expression; 2- Determine how PTEN influences sepsis outcome and morbidities associated with secondary lung infection. 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.

描述（由申请人提供）： 仅在美国每年就有 25 万人因脓毒症死亡。无节制地刺激吞噬细胞可诱发全身炎症反应综合征（SIRS），导致多个系统器官衰竭。长时间的 SIRS 会导致院内感染的易感性增加。吞噬细胞对微生物产物的识别是由 Toll 样受体通过激活 Toll/IL-1R (TIR) 适配器 MyD88 依赖性 NF-kB 激活来介导的。 TLR 激活涉及多种内源性制动器，包括磷酸酶 SHIP-1 和 DUSP。磷酸酶和张力蛋白同源物 PTEN 在控制巨噬细胞活化中的作用及其在控制多种微生物败血症中的作用尚不清楚。该项目基于初步数据，表明 PTEN 通过控制特定 microRNA 的作用来抑制 MyD88 表达。此外，虽然 PTEN 激活对急性脓毒症具有保护作用，但增强和慢性 PTEN 表达会产生有利于内毒素耐受和可能继发感染的有害作用。待检验的假设是，尽管 PTEN 在急性脓毒症早期可防止压倒性的炎症反应，但过度的 PTEN 表达通过损害吞噬细胞中的 TLR 激活，导致脓毒症诱导的免疫麻痹状态的启动和维持。这些研究将增进我们对先天免疫如何发挥作用的全面了解，并将产生关于急性败血症的发病机制和有害条件下继发感染易感性增强的见解。我们提出以下具体目标： 1 - 确定 PTEN 如何控制 MyD88 表达中涉及的转录和转录后修饰； 2-确定 PTEN 如何影响败血症结果和继发性肺部感染相关的发病率。识别脓毒症维持中的特定成分及其作用模式可以确定治疗干预的目标，从而改善宿主脆弱环境中的免疫反应，并可能提出在炎症过度的情况下抑制免疫反应的策略。