PILOT PROJECT: ETOH INDUCED BRAIN INJURY DECREASED BY INHIBITING TIEG2 MEDIATED

试点项目：通过抑制 TIEG2 介导减少 ETH 引起的脑损伤

• 批准号: 8360513
• 负责人: Xiao-Ming Ou
• 金额: $ 4.59万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8360513
• 关键词: Alcohol consumption; Apoptosis; Biochemical; Brain Injuries; Cell Death; Cells; Dexamethasone; Enzymes; Ethanol; Funding; Genes; Grant; Hydrogen Peroxide; Injury; Mediating; Monoamine Oxidase; Monoamine Oxidase B; Monoamine Oxidase Inhibitors; National Center for Research Resources; Neurosciences; Neurotransmitters; Oxygen; Pathway interactions; Pilot Projects; Prevention; Principal Investigator; Production; Reactive Oxygen Species; Reporting; Research; Research Infrastructure; Resources; Source; Stress; Tissues; Toxic effect; Transcription Coactivator; Transforming Growth Factor beta; United States National Institutes of Health; alcohol effect; brain cell; brain tissue; cell injury; cost; inhibitor/antagonist; monoamine; oxidation; stressor

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Long-term stressful situations or heavy ethanol intake induces brain injury; however, the exact biochemical changes that take place in the brain cells/tissues are not yet clear. The long-term objective of this proposal is to understand mechanisms of stress- or ethanol-induced brain tissue injury and to seek its prevention. Transforming growth factor-beta-inducible early gene 2 (TIEG2) is reported to activate monoamine oxidase (MAO) and induce apoptosis. We have found that a cell stressor (dexamethasone; Dex) or ethanol (75 mM) increases TIEG2 expression and causes cell death. One potential pathway is through increasing MAO activity and subsequent reactive oxygen species (ROS) production because MAO is an enzyme that catalyzes the oxidation of monoamine neurotransmitters. The catalytic activity of MAO generates reactive oxygen (H2O2), which is a major intracellular ROS that causes cell toxicity. Therefore, the TIEG2 MAO pathway may be one of mechanisms to contribute stress- or ethanol-induced cell injury. In addition, an MAO B inhibitor (0.25 nM) reduces TIEG2-MAO expression, thus protecting cells from the harmful effects of ethanol. We hypothesize that stress (Dex) or ethanol induces expression of TIEG2, an MAO transcriptional activator. Secondly, we hypothesize that MAO inhibitors can protect against stress- or ethanol-induced brain cell injury by reducing the levels of ROS produced by the TIEG2-MAO cascade.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 长期处于压力状态或大量摄入乙醇会诱发脑损伤；然而，脑细胞/组织中发生的确切生化变化尚不清楚。该提案的长期目标是了解压力或乙醇引起的脑组织损伤的机制并寻求其预防。据报道，转化生长因子-β 诱导的早期基因 2 (TIEG2) 可激活单胺氧化酶 (MAO) 并诱导细胞凋亡。我们发现细胞应激源（地塞米松；Dex）或乙醇（75 mM）会增加 TIEG2 表达并导致细胞死亡。一个潜在的途径是通过增加 MAO 活性和随后的活性氧 (ROS) 产生，因为 MAO 是一种催化单胺神经递质氧化的酶。 MAO 的催化活性会产生活性氧 (H2O2)，这是导致细胞毒性的主要细胞内 ROS。因此，TIEG2 MAO途径可能是应激或乙醇诱导的细胞损伤的机制之一。此外，MAO B 抑制剂 (0.25 nM) 可降低 TIEG2-MAO 表达，从而保护细胞免受乙醇的有害影响。 我们假设压力 (Dex) 或乙醇诱导 TIEG2（一种 MAO 转录激活剂）的表达。其次，我们假设 MAO 抑制剂可以通过降低 TIEG2-MAO 级联产生的 ROS 水平来防止应激或乙醇诱导的脑细胞损伤。