Mechanisms of Alcohol-Induced Tissue Injury

描述(申请人提供)：已有多个实验室表明，组织纤溶酶原激活物(TPA)/纤溶酶系统在兴奋性毒素介导的癫痫发作和海马神经变性中起关键作用。在兴奋性毒性作用下，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。 我们发现，在乙醇处理和EW期间，tPA活性在小鼠海马区和杏仁核中上调，tPA-/-小鼠受到保护，免受EW诱导的癫痫发作和神经变性，就像它们免受刺激毒素注射引起的这些病理变化一样。因此，兴奋性毒素和EW诱导癫痫发作和神经变性的机制(S)至少有一个共同的分子，即tPA。 为了更好地了解电击致癫痫发作和神经变性的机制，我们建议系统地探讨tPA在这些过程中的作用。

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