Understanding genetic basis for resistance to TNF-induced lethal shock using new

使用新方法了解抵抗 TNF 诱导的致死性休克的遗传基础

基本信息

批准号：
7978153
负责人：
Alexander Poltorak
金额：
$ 20.63万
依托单位：
TUFTS UNIVERSITY BOSTON
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-20 至 2012-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7978153
关键词：
Accounting Acute Address Agonist Apoptosis Apoptotic Attenuated Biochemical Cell Death Cells Cessation of life Complement Factor D Data Defect Dose Employee Strikes Equilibrium Exhibits Family member Funding Future Galactosamine Gene Expression Genes Genetic Genetic Models Genomics Health Hepatocyte In Vitro Individual Inflammation Inflammatory Injury Link Lipopolysaccharides Liver Maps Mediating Mediator of activation protein Modeling Mouse Strains Mus Myocardial Infarction Necrosis Pathology Pathway interactions Peritoneal Macrophages Phenotype Phosphotransferases Physiology Reading Receptor Signaling Resistance Septic Shock Shock Signal Transduction Stroke Therapeutic Intervention Time Toxic Shock Syndrome Traumatic Brain Injury Tumor Necrosis Factor Receptor Tumor Necrosis Factor-alpha Tumor Necrosis Factors attenuation base gene cloning genetic analysis genetic linkage analysis in vitro Model in vivo in vivo Model inhibitor/antagonist insight macrophage mortality novel prevent public health relevance response small molecule trait

项目摘要

DESCRIPTION (provided by applicant): Mortality from toxic shock, caused by infective agents that trigger excessive synthesis of tumor necrosis factor (TNF) and other inflammatory molecules by macrophages, remains a major health problem. Here we describe for the first time resistance to lipopolysaccharide (LPS) and TNF-induced death in vivo of wild-derived mice of MSM strain, representing a new genetic model of resistance to toxic shock. The remarkable resistance of these mice to toxic shock is further emphasized by their lack of sensitivity to acute liver injury caused by the co-administration of TNF and D-galactosamine, a well-established in vivo model of endotoxic liver damage. In support of the in vivo resistance data, we show that primary MSM macrophages exhibit another phenotype in that they are resistant to TNF- or TLR-agonists-induced regulated necrosis ("necroptosis") but not apoptosis cell death in vitro. Based on these results, we hypothesize that the two traits are mechanistically linked and propose to examine the connection between necroptosis and toxic shock traits by means of genetic linkage analysis aimed at identification of the loci, which confer both traits. In further extension of the in vitro results, we discovered that TNF-mediated in vivo liver injury can be prevented by a specific inhibitor of a key necroptosis regulator, RIP1 kinase. In addition to cell death phenotype, we demonstrate that TNF synthesis by MSM macrophages is reduced and may also be influenced by RIP1 signaling in vivo. Based on our preliminary data, we suggest that RIP1 kinase is a mediator of acute toxic shock and may represent an important new target for therapeutic intervention. We propose to further characterize the scope of changes in in vitro MSM hepatocyte and macrophage responses to TLR agonists and TNF in order to better determine the cellular basis for MSM resistance to toxic shock. Overall, these studies may provide important new insights into mechanisms of both toxic shock in vivo and necroptotic RIP1 kinase signaling, which has also been implicated in other acute pathologies, such as stroke, myocardial infarction and brain trauma. PUBLIC HEALTH RELEVANCE: Mortality from toxic shock, caused by infective agents that trigger excessive synthesis of tumor necrosis factor (TNF) and other inflammatory molecules by macrophages remains a major health problem. In this proposal, using genetic analysis of resistance to toxic shock in the wild-derived mice, we will reveal novel mechanisms of control of inflammation and its magnitude.

描述（由申请人提供）：由毒性休克引起的死亡率是由触发过度合成肿瘤坏死因子（TNF）和其他巨噬细胞炎症分子引起的，仍然是一个主要的健康问题。在这里，我们首次描述了对脂多糖（LPS）和TNF诱导的MSM菌株野生小鼠的死亡的抗性，这代表了一种对有毒冲击的抗性的新遗传模型。这些小鼠对毒性休克的显着耐药性是由于它们缺乏对TNF和D-半乳糖胺的共同给药引起的急性肝损伤的敏感性，这是一种良好的内毒性肝损害模型。为了支持体内耐药性数据，我们表明原代MSM巨噬细胞表现出另一种表型，因为它们对TNF-或TLR-启动者诱导的调控坏死（“坏死性毒性”）具有抗性，但在体外没有凋亡细胞死亡。基于这些结果，我们假设这两个特征是机械上的联系，并建议通过旨在识别基因座的遗传连锁分析来检查坏死性和有毒休克性状之间的联系，这两个特征赋予了这两个特征。为了进一步扩展体外结果，我们发现TNF介导的体内肝损伤可以通过关键坏死性调节剂RIP1激酶的特定抑制剂来预防体内肝损伤。除了细胞死亡表型外，我们还证明了MSM巨噬细胞的TNF合成降低，也可能受到体内RIP1信号传导的影响。根据我们的初步数据，我们建议RIP1激酶是急性毒性休克的介体，可能代表了治疗干预的重要新目标。我们建议进一步表征体外MSM肝细胞变化的范围和对TLR激动剂和TNF的巨噬细胞反应，以便更好地确定MSM抗毒性休克的细胞基础。总体而言，这些研究可能会为体内有毒休克和坏死性RIP1激酶信号的机制提供重要的新见解，这也涉及其他急性病理，例如中风，心肌梗死和脑外伤。公共卫生相关性：毒性休克的死亡率是由触发过度合成肿瘤坏死因子（TNF）和其他巨噬细胞炎症分子引起的感染剂引起的。在此提案中，使用对野生衍生小鼠中毒性休克的抗性的遗传分析，我们将揭示炎症控制及其大小的新型机制。