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:
- 金额:$ 39.5万
- 依托单位:
- 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:
- 关键词:AcuteAdaptor Signaling ProteinAgonistAnimalsAnti-inflammatoryBacterial InfectionsBindingCessation of lifeCharacteristicsChronicDataDevelopmentDiseaseEndotoxinsEventExhibitsFailureGene SilencingGenetic TranscriptionGoalsHost DefenseHumanImmuneImmune responseImmune systemImmunityImmunosuppressionImpairmentIn VitroInfectionInflammationInflammation MediatorsInflammatoryInflammatory ResponseInjuryInnate Immune ResponseIntensive Care UnitsInterleukin-1 ReceptorsLungMacrophage ActivationMaintenanceMediatingMediator of activation proteinMicroRNAsModelingModificationMolecularMorbidity - disease rateMusMyelogenousNF-kappa BNatural ImmunityNosocomial InfectionsOperative Surgical ProceduresOrganOutcomePTEN genePathogenesisPathway interactionsPatientsPhagocytesPharmacologyPhasePhosphoric Monoester HydrolasesPhosphorylationPredispositionProductionReceptor ActivationRegulatory PathwayRoleSecondary toSepsisSepsis SyndromeSignal PathwaySignal TransductionSmall Interfering RNATLR3 geneTLR4 geneTestingTherapeutic InterventionToll-like receptorsTranscriptional ActivationTranscriptional RegulationTraumaTumor Suppressor ProteinsUnited StatesWorkantimicrobialbaseimprovedin vivoinhibitor/antagonistinsightmRNA Transcript Degradationmacrophagemicrobialmortalitynew therapeutic targetnovelp65pathogenprogramsprotective effectpublic health relevanceresponsesecondary infectionseptictargeted treatmenttherapeutic targettranscription 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):败血症仅在美国每年就造成250,000例死亡。吞噬细胞的无限制刺激可诱导全身炎症反应综合征(SIRS),导致多个全身器官衰竭。延长的SIRS导致对医院感染的易感性增强。微生物产物的吞噬细胞识别是由Toll样受体通过激活Toll/IL-1 R(TIR)衔接子MyD 88依赖性NF-κ B激活介导的。TLR激活中涉及许多内源性制动器,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MyD 88表达。此外,虽然PTEN激活在急性脓毒症中具有保护作用,但增强的和慢性的PTEN表达会产生有害作用,有利于内毒素耐受并可能导致继发感染。待检验的假设是,虽然PTEN在急性脓毒症早期保护抵抗压倒性的炎症反应,但过度的PTEN表达通过损害吞噬细胞中TLR的活化而导致脓毒症诱导的免疫麻痹状态的起始和维持。这些研究将增加我们对先天免疫如何起作用的整体理解,并将产生关于急性脓毒症发病机制和有害条件下继发感染易感性增强的见解。我们提出了以下具体目标:1 -确定PTEN如何控制MyD 88表达中涉及的转录和转录后修饰; 2-确定PTEN如何影响脓毒症结局和继发性肺部感染相关的发病率。鉴定特定组分及其在维持脓毒症中的作用模式可以鉴定用于治疗干预的靶点,从而在宿主脆弱性的环境中改善免疫应答,并且可以建议在过度炎症的环境中抑制免疫应答的策略。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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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: