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

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其他NIH来源。 为子项目列出的总成本可能 表示子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 长期紧张的情况或大量乙醇摄入会导致脑损伤;然而，脑细胞/组织中发生的确切生化变化尚不清楚。这项建议的长期目标是了解应激或乙醇诱导的脑组织损伤的机制，并寻求预防措施。据报道，转化生长因子β诱导早期基因2（TIEG 2）激活单胺氧化酶（MAO）并诱导细胞凋亡。我们已经发现细胞应激物（地塞米松; Dex）或乙醇（75 mM）增加TIEG 2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是催化单胺神经递质氧化的酶。MAO的催化活性产生活性氧（H2 O2），其是导致细胞毒性的主要细胞内ROS。因此，TIEG 2单胺氧化酶通路可能是应激或乙醇诱导细胞损伤的机制之一。此外，MAO B抑制剂（0.25 nM）可降低TIEG 2-MAO表达，从而保护细胞免受乙醇的有害影响。 我们假设应激（Dex）或乙醇诱导TIEG 2（一种MAO转录激活因子）的表达。其次，我们假设单胺氧化酶抑制剂可以通过降低TIEG 2-单胺氧化酶级联反应产生的活性氧水平来防止应激或乙醇诱导的脑细胞损伤。

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.