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

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,败血症每年就造成25万人死亡。无节制地刺激吞噬细胞可诱发系统性炎症反应综合征(SIRS),导致多个全身器官衰竭。SIRS延长导致对医院感染的易感性增加。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介导的。有许多内源性抑制因子参与TLR的激活,包括磷酸酶SHIP-1和DUSP。磷酸酶和紧张素同源物PTEN在控制巨噬细胞活化及其在控制多微生物脓毒症中的作用尚不清楚。该项目基于初步数据,显示PTEN通过控制特定microrna的作用来抑制MyD88的表达。此外,尽管PTEN激活在急性脓毒症中具有保护作用,但PTEN表达增强和慢性表达会产生有害影响,有利于内毒素耐受和可能的继发性感染。需要验证的假设是,尽管PTEN在急性脓毒症早期可以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TLR的激活来启动和维持脓毒症诱导的免疫麻痹状态。这些研究将增加我们对先天免疫如何工作的整体理解,并将对急性脓毒症的发病机制和在有害条件下对继发感染的易感性增加产生见解。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;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。鉴定特定成分及其在维持败血症中的作用模式可能确定治疗干预的目标,从而改善宿主易感环境中的免疫反应,并可能提出在夸大炎症环境中抑制免疫反应的策略。

项目成果

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C. Henrique Serezani其他文献

C. Henrique Serezani的其他文献

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{{ truncateString('C. Henrique Serezani', 18)}}的其他基金

Prostaglandin E2 Actions and Enhanced Susceptibility to Skin Infection in Diabetic Mice
前列腺素 E2 的作用和糖尿病小鼠皮肤感染的易感性增强
  • 批准号:
    9980677
  • 财政年份:
    2020
  • 资助金额:
    $ 39.5万
  • 项目类别:
Prostaglandin E2 Actions and Enhanced Susceptibility to Skin Infection in Diabetic Mice
前列腺素 E2 的作用和糖尿病小鼠皮肤感染的易感性增强
  • 批准号:
    10337275
  • 财政年份:
    2020
  • 资助金额:
    $ 39.5万
  • 项目类别:
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
  • 财政年份:
    2014
  • 资助金额:
    $ 39.5万
  • 项目类别:
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
  • 财政年份:
    2014
  • 资助金额:
    $ 39.5万
  • 项目类别:
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:
    10418725
  • 财政年份:
    2014
  • 资助金额:
    $ 39.5万
  • 项目类别:
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:
    9088490
  • 财政年份:
    2014
  • 资助金额:
    $ 39.5万
  • 项目类别:
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:
    10201714
  • 财政年份:
    2014
  • 资助金额:
    $ 39.5万
  • 项目类别:
Regulation of Toll-like receptor-induced NFkB activation by Gai-coupled receptors
Gai 偶联受体对 Toll 样受体诱导的 NFkB 激活的调节
  • 批准号:
    8646977
  • 财政年份:
    2010
  • 资助金额:
    $ 39.5万
  • 项目类别:
Regulation of Toll-like receptor-induced NFkB activation by Gai-coupled receptors
Gai 偶联受体对 Toll 样受体诱导的 NFkB 激活的调节
  • 批准号:
    8458283
  • 财政年份:
    2010
  • 资助金额:
    $ 39.5万
  • 项目类别:
Regulation of Toll-like receptor-induced NFkB activation by Gai-coupled receptors
Gai 偶联受体对 Toll 样受体诱导的 NFkB 激活的调节
  • 批准号:
    7953238
  • 财政年份:
    2010
  • 资助金额:
    $ 39.5万
  • 项目类别:
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