Mechanisms of Alcohol-Induced Tissue Injury

描述（由申请人提供）：多个实验室表明，组织纤溶酶原激活剂(tPA)/纤溶酶系统对兴奋毒素介导的癫痫发作和海马神经退行性变至关重要。在兴奋性毒性刺激下，tPA激活纤溶酶原产生过量的纤溶酶，然后降解细胞外基质（ECM）的关键成分层粘连蛋白。神经元-基质连接的丧失促进了神经元的死亡，就像其他类型的细胞一样。

DESCRIPTION (provided by applicant): It has been shown in various laboratories that the tissue plasminogen activator (tPA)/plasmin system is critical for excitotoxin-mediated seizures and neurodegeneration in the hippocampus. Upon excitotoxic challenge, tPA activates plasminogen to produce excess plasmin, which then degrades a critical component of the extracellular matrix (ECM), laminin. The loss of the neuron-matrix connection facilitates neuronal death as it does with other cell types. We have found that tPA activity during ethanol treatment and EW is up-regulated in the mouse hippocampus and the amygdala, and that tPA-/- mice are protected from EW-induced seizures and neurodegeneration, as they are from these pathologies induced by excitotoxin injection. Therefore, the mechanism(s) of excitotoxinand EW-induced seizures and neurodegeneration have at least one molecule in common, tPA. To understand better the mechanism of EW-induced seizures and neurodegeneration, we propose to systematically explore the role of tPA in these processes