Alcohol, GILZ and LPS Sepsis

酒精、GILZ 和 LPS 败血症

基本信息

批准号：
9315672
负责人：
GUOSHUN WANG
金额：
$ 17.34万
依托单位：
LSU HEALTH SCIENCES CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-15 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9315672
关键词：
Acute Alcohols Bacterial Toxins Body Temperature Changes Bone Marrow Cause of Death Cells Cessation of life Clinical Management Data Development Dose Ethanol Future Gene Expression Genes Genetic Transcription Glucocorticoids Gram-Negative Bacterial Infections Hematopoietic stem cells Immune Immune response Immunosuppression Intensive Care Intervention Intoxication Isopropanol Laboratories Lentivirus Vector Leucine Zippers Light Link Lipopolysaccharides Marrow Measures Mediating Medicine Molecular Molecular Target Mus Pathogenesis Play Property Publishing Research Resistance Role Sepsis Sepsis Syndrome Septic Shock Serum Severities Small Interfering RNA Staphylococcal Enterotoxin B Testing Toxin Transplantation United States Work adverse outcome alcohol exposure animal mortality attenuation cytokine effective therapy genetic analysis mortality new therapeutic target novel protective effect reconstitution septic therapeutic development

项目摘要

ABSTRACT Sepsis is a major cause of mortality worldwide. Approximately 250,000 sepsis-resulted deaths occur each year in the United States alone. In spite of vigorous research, molecular understanding of this systemic inflammatory response syndrome is not complete. A common type of sepsis results from lipopolysaccharide (LPS) intoxication from Gram-negative bacterial infection. The latest genetic analyses on LPS resistance in mice reveal the critical role of Glucocorticoid-Induced Leucine Zipper (GILZ) in protection against LPS-induced sepsis. We recently discovered that acute ethanol exposure upregulates GILZ expression, and protects mice from LPS septic shock. Moreover, research by others indicates that isopropanol protects mice from Staphylococcal enterotoxin B-induced septic shock. These findings prompt us to seek the potential link between alcohol activation of the GILZ gene and alcohol attenuation of the sepsis induced by LPS and SEB. The overall hypothesis is that GILZ in marrow-derived immune cells is pivotal to alcohol protection against sepsis induced by bacterial toxins, and the short-chain alcohols that are structurally close to ethanol share the same mechanism for immunosuppression. Two specific aims are proposed for this R21 application: 1) to test the hypothesis that GILZ depletion in marrow-derived immune cells abrogates ethanol protection against septic shock induced by LPS and SEB; 2) to examine the prediction that the short-chain alcohols which are structurally close to ethanol share the same properties of upregulating GILZ expression and protecting against septic shock induced by LPS and SEB. Completion of this project will determine whether GILZ is a key regulator controlling the host immune response to the bacterial toxins. Molecular understanding of this mechanism will define new therapeutic targets for better intervention of sepsis.

抽象的脓毒症是全世界死亡的主要原因。大约有 250,000 人死于败血症每年仅在美国。尽管进行了积极的研究，但对这一点的分子理解全身炎症反应综合征并不完全。脓毒症的一种常见类型是由革兰氏阴性细菌感染引起的脂多糖（LPS）中毒。最新的基因分析小鼠的 LPS 抵抗揭示了糖皮质激素诱导的亮氨酸拉链 (GILZ) 在保护中的关键作用对抗 LPS 引起的败血症。我们最近发现急性乙醇暴露会上调 GILZ 表达，并保护小鼠免受 LPS 感染性休克。此外，其他人的研究表明异丙醇可保护小鼠免受葡萄球菌肠毒素 B 诱导的败血性休克。这些发现提示我们寻找 GILZ 基因的酒精激活与酒精减弱之间的潜在联系 LPS 和 SEB 诱导的败血症。总体假设是骨髓源性免疫细胞中的 GILZ 对于酒精预防细菌毒素引起的败血症至关重要，并且短链结构上与乙醇相似的醇具有相同的免疫抑制机制。为此 R21 应用提出了两个具体目标：1) 检验 GILZ 耗尽的假设骨髓源性免疫细胞消除乙醇对 LPS 和 SEB 引起的感染性休克的保护作用； 2）检验结构上与乙醇相似的短链醇的预测上调 GILZ 表达并防止 LPS 诱导的败血性休克具有相同的特性 SEB。该项目的完成将确定GILZ是否是控制宿主免疫的关键调节因子对细菌毒素的反应。对这一机制的分子理解将定义新的治疗方法更好地干预脓毒症的目标。