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:10418725
- 负责人:
- 金额:$ 55.66万
- 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 2023-06-30
- 项目状态:已结题
- 来源:
- 关键词:Academic Medical CentersAcute Lung InjuryAnimalsAnti-Inflammatory AgentsApoptosisBindingBloodBlood VesselsButyratesCellsCessation of lifeComplexDataDevelopmentDiseaseEnsureEnvironmentEnzymesEquilibriumEventExhalationExhibitsFatty AcidsGene ExpressionGenerationsGeneticGenetic TranscriptionGlycolysisGoalsHomeostasisHost DefenseHumanHydroxyl RadicalIL18 geneIL1R1 geneImmuneImmune responseImmunologyIndividualInfiltrationInflammasomeInflammationInflammation MediatorsInflammatoryInflammatory ResponseIntensive Care UnitsInterleukin-1 betaLeadLeukocytesLipidsLungMaintenanceMediatingMedicineMetabolicMetabolic PathwayMicroRNAsMolecularMolecular TargetMorbidity - disease rateMusMyelogenousMyeloid CellsNonesterified Fatty AcidsNosocomial InfectionsNucleotidesOperative Surgical ProceduresOrganOrgan failureOutcomePTEN genePathway interactionsPersonsPhagocytesPhosphorylationPlant RootsPredispositionProductionProtein phosphatasePublishingPulmonary InflammationRNA StabilityRespiratory FailureRoleSepsisSeriesSerumSeverity of illnessShapesSignal TransductionSiteSyndromeSystemic Inflammatory Response SyndromeSystemic infectionTechniquesTestingTherapeuticTherapeutic InterventionTissuesTraumaUntranslated RNAWorkantimicrobialarmcytokineexperienceexperimental studyfatty acid metabolismfatty acid oxidationgain of functionimprovedinhibitorinsightlung injurymacrophagemetabolic profilemortalityneutrophilnovelnovel therapeuticsorgan injurypleiotropismpolymicrobial sepsispre-clinicalpreventprogramsreceptorseptictargeted treatmenttissue injury
项目摘要
SUMMARY:
Sepsis is a significant cause of morbidity and mortality. Severe sepsis complicated with multiple organ injury and
acute lung injury (ALI)-induced respiratory failure frequently serves as a direct reason of death. During sepsis,
unrestrained stimulation of leukocytes and structural cells can induce Systemic Inflammatory Response
Syndrome (SIRS) resulting in tissue injury and susceptibility to nosocomial infection. Unfortunately, as no
effective medicine is available to treat the developing SIRS/organ injury in these individuals, there is a strong
need to further dissect the complex events that lead to the initiation and progression of SIRS. The long-term goal
of this project is to identify endogenous inhibitors of phagocyte function that could decrease different arms of the
inflammatory response while restoring antimicrobial effector functions. This renewal is built upon published and
preliminary data generated while investigating the role of the phosphatase and tensin homolog PTEN in
microRNA-mediated MyD88 degradation and the generation of SIRS during sepsis. We found that PTEN
deficiency enhances mortality in septic mice; that miR21 (a microRNA that targets PTEN) is a homeostatic
regulator of macrophage inflammatory response and that preventing excessive glycolysis decreases SIRS
development, ALI formation and improves animal survival. Our preliminary data suggest that in addition to
controlling transcriptional programs, PTEN also directly inhibits the inflammasome (intracellular inflammatory
platforms)-dependent release of potent inflammatory mediators. PTEN also stimulates fatty acid oxidation (FAO),
which inhibits inflammation. Furthermore, we also found that miR21 inhibits the expression of genes involved in
FAO, which correlates with decreased animal survival, increased lung inflammation and mortality. From these
findings, we formulated our central hypothesis that during sepsis, myeloid-specific signaling along the
miR21/PTEN/FAO axis becomes dysregulated and drives lung injury and lethality during sepsis. This hypothesis
will be examined by testing the 1) role of PTEN in inflammasome activation in phagocytes in sepsis and 2)
Determine the role of the miR21/PTEN axis in lung injury and mortality during sepsis. We will employ a series of
state-of-the-art techniques, along with epistatic and gain of function approaches to unveil new signaling programs
that ultimately might influence ALI and mortality during systemic infections. The combination of the PI’s
experience in sepsis, lung immunology and inflammation, the assembled team of collaborators, and the
environment at Vanderbilt University Medical Center ensure that this work will be accomplished. 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.
概括:
脓毒症是发病和死亡的重要原因。严重败血症并发多脏器损伤
急性肺损伤(ALI)引起的呼吸衰竭常常是死亡的直接原因。在败血症期间,
无限制地刺激白细胞和结构细胞可诱发全身炎症反应
综合征(SIRS)导致组织损伤和医院感染易感性。不幸的是,由于没有
可以使用有效的药物来治疗这些个体中正在发生的 SIRS/器官损伤,
需要进一步剖析导致 SIRS 发生和进展的复杂事件。长期目标
该项目的目的是确定吞噬细胞功能的内源性抑制剂,这些抑制剂可以减少吞噬细胞的不同臂
炎症反应,同时恢复抗菌效应功能。此次更新是建立在已发布和
在研究磷酸酶和张力蛋白同源物 PTEN 的作用时生成的初步数据
脓毒症期间 microRNA 介导的 MyD88 降解和 SIRS 的产生。我们发现PTEN
缺乏会增加脓毒症小鼠的死亡率; miR21(一种靶向 PTEN 的 microRNA)是一种稳态
巨噬细胞炎症反应的调节剂,防止过度糖酵解可减少 SIRS
发育、ALI 形成并提高动物生存率。我们的初步数据表明,除了
PTEN 控制转录程序,还直接抑制炎症小体(细胞内炎症
平台)依赖性强效炎症介质的释放。 PTEN 还刺激脂肪酸氧化 (FAO),
从而抑制炎症。此外,我们还发现miR21抑制相关基因的表达
粮农组织,这与动物存活率下降、肺部炎症和死亡率增加有关。从这些
研究结果表明,我们提出了我们的中心假设,即在脓毒症期间,骨髓特异性信号传导沿着
脓毒症期间 miR21/PTEN/FAO 轴失调并导致肺损伤和死亡。这个假设
将通过测试 1) PTEN 在脓毒症吞噬细胞炎症小体激活中的作用和 2) 进行检查
确定 miR21/PTEN 轴在脓毒症期间肺损伤和死亡率中的作用。我们将聘用一系列
最先进的技术,以及上位和功能获得方法来揭示新的信号转导程序
最终可能会影响全身感染期间的 ALI 和死亡率。 PI 的组合
在脓毒症、肺部免疫学和炎症方面的经验、合作者组成的团队以及
范德比尔特大学医学中心的环境确保了这项工作的完成。这
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目标
治疗干预可改善宿主脆弱环境中的免疫反应,并可能
提出了在炎症过度的情况下抑制免疫反应的策略。
项目成果
期刊论文数量(22)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
SOCS-1 inhibition of type I interferon restrains Staphylococcus aureus skin host defense.
I型干扰素抑制SOCS-1抑制金黄色葡萄球菌皮肤宿主防御。
- DOI:10.1371/journal.ppat.1009387
- 发表时间:2021-03
- 期刊:
- 影响因子:6.7
- 作者:Klopfenstein N;Brandt SL;Castellanos S;Gunzer M;Blackman A;Serezani CH
- 通讯作者:Serezani CH
Opposing roles of LTB4 and PGE2 in regulating the inflammasome-dependent scorpion venom-induced mortality.
- DOI:10.1038/ncomms10760
- 发表时间:2016-02-23
- 期刊:
- 影响因子:16.6
- 作者:Zoccal KF;Sorgi CA;Hori JI;Paula-Silva FW;Arantes EC;Serezani CH;Zamboni DS;Faccioli LH
- 通讯作者:Faccioli LH
MicroRNA 21 is a homeostatic regulator of macrophage polarization and prevents prostaglandin E2-mediated M2 generation.
- DOI:10.1371/journal.pone.0115855
- 发表时间:2015
- 期刊:
- 影响因子:3.7
- 作者:Wang Z;Brandt S;Medeiros A;Wang S;Wu H;Dent A;Serezani CH
- 通讯作者:Serezani CH
Innate Immunity to Staphylococcus aureus: Evolving Paradigms in Soft Tissue and Invasive Infections.
- DOI:10.4049/jimmunol.1701574
- 发表时间:2018-06-15
- 期刊:
- 影响因子:0
- 作者:Brandt SL;Putnam NE;Cassat JE;Serezani CH
- 通讯作者:Serezani CH
PAFR activation of NF-κB p65 or p105 precursor dictates pro- and anti-inflammatory responses during TLR activation in murine macrophages.
- DOI:10.1038/srep32092
- 发表时间:2016-08-24
- 期刊:
- 影响因子:4.6
- 作者:Ishizuka EK;Filgueiras LR;Rios FJ;Serezani CH;Jancar S
- 通讯作者:Jancar S
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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:
$ 55.66万 - 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:
$ 55.66万 - 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:
$ 55.66万 - 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:
$ 55.66万 - 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:
$ 55.66万 - 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:
$ 55.66万 - 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:
9332397 - 财政年份:2014
- 资助金额:
$ 55.66万 - 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:
$ 55.66万 - 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:
$ 55.66万 - 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:
$ 55.66万 - 项目类别:
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