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：
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
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/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

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，败血症每年就会占25万人死亡。吞噬细胞的不受约束刺激会诱导全身性炎症综合征（SIR），导致多个全身器官失败。长时间的SIRS导致对医院感染的敏感性增强。通过激活Toll/IL-1R（TIR）适配器MyD88依赖性NF-KB激活，通过TOLL类似受体介导的微生物产物的吞噬细胞识别。 TLR激活涉及许多内源制动器，包括磷酸酶Ship-1和DUSP。磷酸酶和tensin同源物在控制巨噬细胞激活及其在控制多成菌败血症中的作用的作用尚不清楚。该项目基于初步数据，该数据表明PTEN通过控制特定microRNA的作用来抑制MyD88的表达。此外，虽然PTEN激活在急性败血症中具有保护作用，但增强和慢性PTEN表达会产生有害的效果，有利于内毒素耐受性和可能的继发感染。要测试的假设是，尽管PTEN在急性败血症的早期预防了压倒性的炎症反应，但过度的PTEN表达是造成脓毒症诱导的免疫分析态的起始和维持，通过损害吞噬细胞中的TLR激活。这些研究将提高我们对先天免疫的工作原理的整体理解，并就急性败血症的发病机理以及在有害条件下对继发感染的易感性提高。我们提出以下特定目的：1-确定PTEN如何控制MyD88表达中涉及的转录和转录后修改； 2-确定PTEN如何影响与继发性肺部感染相关的败血症结果和病因。鉴定特定成分及其在维持败血症方面的作用方式可能会识别治疗干预的靶标，从而提高宿主脆弱性环境中的免疫反应性，并可能提出策略，以抑制夸张的炎症环境中的免疫反应。