Mechanisms of Alcohol-Induced Tissue Injury

描述（由申请人提供）：在多个实验室中已经显示，组织纤溶酶原激活物（tPA）/纤溶酶系统对于海马中兴奋性毒素介导的癫痫发作和神经变性至关重要。在兴奋性毒性激发后，tPA激活纤溶酶原以产生过量的纤溶酶，其然后降解细胞外基质（ECM）的关键组分层粘连蛋白。神经元-基质连接的丧失促进神经元死亡，就像其他细胞类型一样。 我们已经发现，tPA活性在乙醇处理和EW是上调的小鼠海马和杏仁核，和tPA-/-小鼠受到保护，从EW诱导的癫痫发作和神经变性，因为它们是从这些由兴奋毒素注射诱导的病理。因此，兴奋性毒素和EW诱导的癫痫发作和神经退行性变的机制至少有一个共同的分子，tPA。 为了更好地理解EW诱发癫痫发作和神经退行性变的机制，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