Mechanisms of Alcohol-Induced Tissue Injury

酒精引起的组织损伤的机制

• 批准号: 7056215
• 负责人: SIDNEY STRICKLAND
• 金额: $ 42.09万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-20 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7056215
• 关键词: convulsions; drug withdrawal; ethanol; hippocampus; laboratory mouse; laminin; metalloendopeptidases; neural degeneration; neuroprotectants; neurotoxins; pathologic process; plasminogen; plasminogen activator; protease inhibitor; tissue /cell culture

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

描述（由申请人提供）：在各种实验室中都表明，组织纤溶酶原激活剂（TPA）/纤溶酶系统对于海马中的兴奋毒素介导的癫痫发作和神经变性至关重要。在兴奋毒性挑战时，TPA激活纤溶酶原以产生过量的纤溶酶，然后降解细胞外基质（ECM），层粘连蛋白的关键成分。神经元 - 矩阵连接的丧失促进了神经元死亡，就像其他细胞类型一样。 我们发现，在小鼠海马和杏仁核中乙醇处理过程中的TPA活性在上调，并且TPA - / - 小鼠受到EW诱导的癫痫发作和神经变性的保护，因为它们是从兴奋蛋白摄取诱导的这些病理学中受到的。因此，兴奋毒素和EW诱导的癫痫发作和神经变性的机制至少具有一个共同的分子TPA。 为了更好地了解EW诱导的癫痫发作和神经变性的机制，我们建议系统地探索TPA在这些过程中的作用