Ethanol & Infection on Mitochondrial Death Signaling

乙醇

• 批准号: 7062749
• 负责人: STEPHEN P KANTROW
• 金额: $ 15.1万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7062749
• 关键词: BCL2 gene /protein; CD95 molecule; apoptosis; bacteria infection mechanism; bacterial pneumonia; biological signal transduction; chronic disease /disorder; cysteine endopeptidases; cytochrome c; ethanol; gene deletion mutation; genetically modified animals; glutathione; host organism interaction; immunosuppressive; laboratory mouse; lymphocyte; mitochondria; oxidative stress; pathologic process; spleen; thymus

Immune activation during severe infection is accompanied by widespread lymphocyte apoptosis. In animal models of lethal infection, lymphocyte apoptosis appears to compromise the host, as strategies to oppose apoptosis improve survival. Alcoholism is associated with an increased risk of severe infection, and depletion of lymphocytes in spleen and thymus dudng chronic ethanol consumption is well recognized. Because ethanol and infection can increase oxidative stress to mitochondria, and mitochondria are central regulators of apoptosis, we hypothesize that ethanol consumption increases mitochondrial injury and death signaling in lymphocytes during infection. We propose to study the effects of chronic ethanol exposure on lymphoid tissue injury during infection with Streptococcus pneumoniae, a common cause of bacteremia in alcoholism and HIV infection. In Specific Aim 1, we will determine the effects of ethanol feeding on apoptosis in 1) spleen and thymus during pneumococcal infection in vivo and 2) splenocytes exposed to a relevant death signal, Fas ligand, in vitro. In Specific Aim 2, we will measure the effects of ethanol feeding and pneumococcal infection on mitochondrial glutathione content and oxidative injury to mitochondrial DNA in lymphoid tissue. In Specific Aim 3, we will evaluate two mitochondria-based strategies for opposing lymphocyte apoptosis in this model by 1) utilizing bcl-2 over-expressing transgenic mice and 2) supplementing mitochondrial glutathione. The results of these experiments will increase our understanding of how chronic ethanol exposure compromises lymphoid tissues directly and during the acute stress of infection.

严重感染期间的免疫激活伴随着广泛的淋巴细胞凋亡。在致命感染的动物模型中，淋巴细胞凋亡似乎会损害宿主，因为 反对凋亡的策略提高了生存。酒精中毒与脾脏和胸腺dudng慢性乙醇的严重感染风险增加以及淋巴细胞的消耗有关 消费良好。因为乙醇和感染可以增加氧化应激 线粒体和线粒体是凋亡的核心调节剂，我们假设乙醇 消费增加了线粒体损伤和淋巴细胞中的死亡信号传导 感染。我们建议研究慢性乙醇暴露对淋巴组织损伤的影响 在肺炎链球菌感染期间，酒精中毒和HIV感染中菌血症的常见原因。在特定目标1中，我们将确定乙醇对体内肺炎球菌感染期间脾脏和胸腺凋亡的影响，以及2）暴露于相关死亡信号的脾细胞，体外。在特定目标2中，我们将测量乙醇喂养和肺炎球菌感染对淋巴组织中线粒体DNA的线粒体谷胱甘肽含量和氧化损伤的影响。在特定的目标3中，我们将通过1）利用Bcl-2过表达的转基因小鼠和2）补充线粒体谷胱甘肽来评估该模型中相对淋巴细胞凋亡的两种基于线粒体的策略。这些实验的结果将增加我们对慢性乙醇暴露如何损害淋巴组织如何直接和在感染的急性应激期间的理解。