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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

基本信息

批准号：
9332397
负责人：
C. Henrique Serezani
金额：
$ 39.5万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
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/9332397
关键词：
Acute Adaptor Signaling Protein Agonist Animals Anti-inflammatory Bacterial Infections Binding Cessation of life Characteristics Chronic Data Development Disease Endotoxins Event Exhibits Failure Gene Silencing Genetic Transcription Goals Host Defense Human Immune Immune response Immune system Immunity Immunosuppression Impairment In Vitro Infection Inflammation Inflammation Mediators Inflammatory Inflammatory Response Injury Innate Immune Response Intensive Care Units Interleukin-1 Receptors 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 Pharmacology Phase Phosphoric Monoester Hydrolases Phosphorylation Predisposition Production Receptor Activation Regulatory Pathway Role Secondary to Sepsis Sepsis Syndrome Signal Pathway Signal Transduction Small Interfering RNA TLR3 gene TLR4 gene Testing Therapeutic Intervention Toll-like receptors Transcriptional Activation Transcriptional Regulation Trauma Tumor Suppressor Proteins United States Work antimicrobial base improved in vivo inhibitor/antagonist insight mRNA Transcript Degradation macrophage microbial mortality new therapeutic target novel p65 pathogen programs protective effect public health relevance response secondary infection septic targeted treatment therapeutic target transcription factor

项目摘要

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25万人死于败血症。无节制地刺激吞噬细胞可诱发全身性炎症反应综合征(SIRS)，导致多系统器官衰竭。长时间的全身炎症反应综合征会增加医院感染的易感性。Toll样受体通过激活Toll/IL-1R(TIR)接头MyD88依赖的NF-kB激活介导对微生物产品的吞噬细胞识别。有许多内源性的刹车参与TLR的激活，包括磷酸酶SHIP-1和DUSP。磷酸酶和张力蛋白同源物PTEN在控制巨噬细胞激活中的作用以及它在控制多菌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microRNAs的作用来抑制MyD88的表达。此外，虽然PTEN激活在急性脓毒症中具有保护作用，但增强和慢性PTEN表达会产生有害的影响，有利于内毒素耐受和可能的继发感染。需要检验的假设是，尽管PTEN在急性脓毒症早期可以保护机体免受压倒性的炎症反应，但PTEN的过度表达通过损害吞噬细胞中TLR的激活而导致脓毒症诱导的免疫麻痹状态的启动和维持。这些研究将增加我们对先天免疫如何工作的全面了解，并将对急性脓毒症的发病机制和在有害条件下增加继发感染的易感性产生深刻的见解。我们提出了以下具体目标：1-确定PTEN如何控制涉及MyD88表达的转录和转录后修饰；2-确定PTEN如何影响败血症结局和继发性肺部感染相关的发病率。对脓毒症维持中特定成分及其作用模式的识别可以确定治疗干预的靶点，从而在宿主易受攻击的环境中提高免疫反应性，并可能建议在过度炎症环境中抑制免疫反应的策略。