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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：
10418725
负责人：
C. Henrique Serezani
金额：
$ 55.66万
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 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10418725
关键词：
Academic Medical Centers Acute Lung Injury Animals Anti-Inflammatory Agents Apoptosis Binding Blood Blood Vessels Butyrates Cells Cessation of life Complex Data Development Disease Ensure Environment Enzymes Equilibrium Event Exhalation Exhibits Fatty Acids Gene Expression Generations Genetic Genetic Transcription Glycolysis Goals Homeostasis Host Defense Human Hydroxyl Radical IL18 gene IL1R1 gene Immune Immune response Immunology Individual Infiltration Inflammasome Inflammation Inflammation Mediators Inflammatory Inflammatory Response Intensive Care Units Interleukin-1 beta Lead Leukocytes Lipids Lung Maintenance Mediating Medicine Metabolic Metabolic Pathway MicroRNAs Molecular Molecular Target Morbidity - disease rate Mus Myelogenous Myeloid Cells Nonesterified Fatty Acids Nosocomial Infections Nucleotides Operative Surgical Procedures Organ Organ failure Outcome PTEN gene Pathway interactions Persons Phagocytes Phosphorylation Plant Roots Predisposition Production Protein phosphatase Publishing Pulmonary Inflammation RNA Stability Respiratory Failure Role Sepsis Series Serum Severity of illness Shapes Signal Transduction Site Syndrome Systemic Inflammatory Response Syndrome Systemic infection Techniques Testing Therapeutic Therapeutic Intervention Tissues Trauma Untranslated RNA Work antimicrobial arm cytokine experience experimental study fatty acid metabolism fatty acid oxidation gain of function improved inhibitor insight lung injury macrophage metabolic profile mortality neutrophil novel novel therapeutics organ injury pleiotropism polymicrobial sepsis pre-clinical prevent programs receptor septic targeted treatment tissue 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：
PLoS pathogens
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：
Nature communications
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.